Ebook Medical genetics at a glance (3rd edition): Part 2

(BQ) Part 2 book Medical genetics at a glance presents the following contents: Embryology and congenital abnormalities, multifactorial inheritance and twin studies, cancer, biochemical genetics, immunogenetics, molecular diagnosis, genetic counselling, disease management, ethical and social issues.

41 Human embryology in outline Figure 41.1 Fertilization and implantation (uterus not to scale) Blastomeres Anaphase of first cleavage division 2-cell stage 30 hours Zygote Male pro-nucleus Female pro-nucleus Discarded zona pellucida First polar body Zona pellucida Corona radiata Fertilization Day Implantation Day Syncytiotrophoblast Cytotrophoblast Formation of the embryonic disc Day Endometrium Uterine wall Secondary oocyte at metaphase Perivitelline space Blastocyst Day Trophectoderm or trophoblast Blastocoel Cortical reaction Cortical granules Ampulla Figure 41.3 Day 18 Syncytiotrophoblast Amniotic cavity Hypoblast (primitive endoderm) Epiblast (primitive ectoderm) Day 18 Embryonic disc Dorsal view A Primitive node Cranial end Primitive groove Day 19 Blastocyst cavity Figure 41.4 Pattern of neural tube closure (21–28 days) Transverse section along line A–A Caudal end A Endometrium Inner cell mass, or embryoblast Uterine tube Second polar body Figure 41.2 Morula Day Amniotic cavity Epiblast Movement of node A Notochordal process Neural folds Cytotrophoblast Primitive node Day 20 A Neural crests A A Hypoblast Neural plate Notochordal process Day 22 Embryonic disc, sagittal section along cranio-caudal axis Medical Genetics at a Glance, Third Edition Dorian J Pritchard and Bruce R Korf 106  © 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd A A Somites Neural crest cells Somite Neural tube –2 weeks –14 days 0 14 Cleavage Gastrulation 28 Organogenesis 42 Bi rt h He a M rt b aj e or at or st ga a ns rts fo rm ed clo se Ne ur al tu be be Ov u Fe lat rt ion iliz at ion Im pla nt at ion G as tr ula tio n ru al st m en M id - Time d gin s Time scale of embryogenesis flo w Figure 41.5 38 weeks 266 days 56 Cytodifferentiation and growth Somitogenesis Neurulation Gametes Pre-embryo Embryo Fetus Infant Overview The embryo (weeks 2–8) Fertilization by a sperm initiates embryogenesis Mitosis ensues and the pre-embryo implants in the uterus The embryo proper develops from a few internal cells, through creation of three embryonic germ layers Organogenesis involves interactions between these and is completed by 6–8 weeks During the subsequent period of growth and cytodifferentiation the individual is called a fetus Gastrulation is the process that creates the embryonic mesoderm and initiates activity of the embryo’s own genes The primitive streak first appears in the epiblast at the caudal (tail) end of the embryonic disc, extends towards its centre and then develops the primitive groove in its amniotic (i.e dorsal) surface At the cranial (head) end of this develops the primitive (or Hensen’s) node Epiblast cells migrate across the disc, through the primitive groove and into the space above the hypoblast These become the embryonic mesoderm, creating the three germ layers: ectoderm from the epiblast, mesoderm, and endoderm from the hypoblast together with some epiblast cells that merge with it Mesoderm cells that migrate anteriorly and accumulate in the midline form the notochordal process, which later extends caudally The epiblast thickens to form the neural plate and a neural fold arises on either side of the central axis These curve over, contact and from 22 days fuse in five separate movements to create the neural tube, which later becomes the spinal cord Along the dorsal edges of the neural folds are the neural crest cells that migrate out to give rise to several cell types: nerve, bone, supporting structures of the heart, adrenalin-secreting and pigment cells, etc As the primitive node moves caudally down the midline, blocks of mesoderm on either side rotate to create 42–44 pairs of segmental somites, the most caudal five to seven of which subsequently disappear (see Chapter 42) The pre-embryo (weeks 0–2) The secondary oocyte is shed into the peritoneal cavity and directed into the adjacent uterine (Fallopian) tube, where fertilization must take place within 24 hours The sperm performs four functions: (i) stimulation of metaphase II in the secondary oocyte; (ii) restoration of the diploid number of chromosomes; (iii) initiation of cleavage; and (iv) determination of sex The sperm passes through the corona cells on the oocyte sur­face and adheres to the zona pellucida The acrosome in the sperm head then releases enzymes that digest a tunnel through the zona pellucida, allowing the sperm to pass into the perivitelline space and fuse with the oocyte membrane The sperm head is then engulfed by the oocyte and entry of more sperm prevented by a rapid cortical reaction The oocyte nucleus completes metaphase II, expels the second polar body and maternal and paternal pro-nuclei fuse to form the zygote Mitosis of the pre-embryo is called cleavage and the resultant blastomeres are smaller after each division The 16-cell morula passes down the uterine tube aided by peristalsis and ciliary movement A space called the blastocoel forms off-centre in the morula to create the blastocyst, which swells and bursts from the zona pellucida Two different cell types are now recognizable, the flattened trophectoderm cells of the outer trophoblast and an eccentrically placed inner cell mass or embryoblast On day the blastocyst implants in the endometrium lining the uterus Some trophoblast cells fuse to form the invasive syncytiotrophoblast, the remainder constituting the cytotrophoblast The blastocyst now takes nourishment from the mother and grows rapidly as it sinks further into the endometrium The inner cell mass exposed ventrally to the blastocoel flattens to form the primitive endoderm, or hypoblast, while the remainder forms the primitive ectoderm, or epiblast, within which develops the amniotic cavity The double-layered disc called the embryonic disc forms from the epiblast and hypoblast at 7–12 days, from which the embryo proper develops The fetus (weeks 8–38) The ectoderm is the origin of the outer epithelium and CNS and, with mesoderm, peripheral structures such as the limbs; mesoderm forms muscles, circulatory system, kidneys, sex organs and together with endoderm, the internal organs; endoderm gives rise to the gut and digestive glands The rudiments of all the major organs are formed through ‘inductive’ tissue interactions by about weeks, when the heart starts beating Thereafter development mainly involves increase in the number and types of cells Expected date of delivery (EDD) Birth is generally considered to occur at 38 weeks from conception, or 40 weeks (280 days) from the first day of the woman’s last normal menstrual period (LMP) There are variations among women in cycle length and times of ovulation, the modal EDD being around 283 days from the LMP This has important implications with respect to birth induction; modern practice favours final dating by ultrasound Human embryology in outline  Embryology and congenital abnormalities  107 42 Figure 42.1 Body patterning Structure of the four paralogous HOX clusters Order of expression is from the right (3') to left (5') 5' HOXA Chr.7p14 A13 A11 A10 A9 A7 A6 HOXB Chr.17q21 B13 B9 B8 B7 B6 HOXC Chr.12q13 C13 C12 C11 C10 C9 C8 C6 HOXD Chr.7q31 D13 D12 D11 D10 D9 D8 Figure 42.3 Figure 42.2 Pattern of migration of neural crest cells into the branchial arches 3' A5 A4 A3 A2 A1 B5 B4 B3 B2 B1 C5 C4 Rhombomeres r4 r3 r7 r6 r5 643 D4 D3 D1 Branchial arches Anterior expression limits of the HOX genes in the early CNS Rhombomeres r9 r8 r7 r6 r5 r4 r3 r2 r1 Developmental fates of the branchial arches Figure 42.4 Hindbrain Midbrain Figure 42.5 Overlapping expression patterns of the four HOX gene clusters HOX gene expression Figure 42.6 Nasal processes Palate Incus Facial cartilage Stapes Forebrain 10 11 12 Thymus Hyoid Figure 42.7 A–P axis definition in the limb bud Cytoplasmic retinoic acid receptor source Mesenchyme Anterior Apical ectodermal ridge (AER) expresses FGF2, FGF4, FGF8, p63, TBX genes 13 r-Fng + Wnt7a expression in dorsal ectoderm Distal Ventral Proximal Posterior AER forms at dorsoventral interface Mesenchymal condensates in the forelimb TBX5 expression Distal Progress zone Zone of polarizing activity (ZPA) Figure 42.8 Humerus Distal Proximal Mandible Malleus External auditory meatus Anterior Dorsal Optic vesicle Parathyroids P–D, D–V axis definition in the limb bud Proximal Posterior En-1 expression in ventral ectoderm Medical Genetics at a Glance, Third Edition Dorian J Pritchard and Bruce R Korf 108  © 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd 12 Radius Zones of HOXD 10 expression in 11 mesenchyme ZPA expresses Shh, BMPs, GLI3 TBX3 expression Anterior Ulna Posterior Mesenchymal condensates corresponding to phalanges Overview The human body shows regular features of anatomical organization that constitute what is known as ‘body patterning’ Many of the important genes involved code for RNA transcription factors that bind to DNA, or protein morphogens that bind to cell surface receptors on target tissues Some of the gene names seem bizarre, as they are derived from research on other species Genes identified in non-human species are conventionally written in lower case, with an upper case capital if dominant (e.g Shh), the equivalent human genes being written in upper case (e.g SHH) The main body Differentiation along the antero-posterior axis The antero-posterior axis is defined by the primitive streak, initiation and maintenance of which relates to the caudal movement of the primitive node and the sequential expression of members of four gene clusters, HOXA, B, C and D Each cluster contains a very similar series of up to 13 genes encoding transcription factors, each containing the homeobox DNA binding domain HOX genes located at the 3′ (number 1) end are expressed earlier than those located 5′ and there is direct linear correlation between the position of each HOX gene in its cluster and its temporal and spatial expression This derives from the graded sensitivity of gene expression controlling sequences to a common control molecule Primitive node function requires expression of the Nodal gene and its associated morphogen is believed to be retinoic acid, which it secretes increasingly abundantly as it moves in the caudal direction More posterior target cells are thus exposed to larger concentrations of retinoic acid, with progressive activation of more HOX genes The fate of the neural crest (NC) cells is defined by the specific HOX genes that are active at their origin NC cells from the fore- and midbrain migrate and differentiate into the mesenchyme of the first pharyngeal pouch, those of the anterior hindbrain to the mesenchyme of the second pharyngeal pouch Cervical NC cells move into the third, fourth and sixth pharyngeal arches The first embryonic pharyngeal arch forms the mandible and malleus, the first cleft the external auditory meatus and the mesenchyme of the first pharyngeal pouch, the nasal processes, palate and incus The second arch forms part of the hyoid apparatus, the stapes and facial cartilage The third arch also contributes to the hyoid cartilage The third and fourth pouches become the thymus and parathyroids The fourth and sixth arches form the laryngeal cartilages, the fifth arch degenerates The blood vessels within the arches form the aortic and pulmonary systems There is evidence that the gene TBX1 may be important specifically for the arteries of the fourth arch, and DiGeorge syndrome, with partial absence of the thymus and facial malformation, etc (see Chapter 39) is due to a Chromosome 22 microdeletion involving TBX1 Differentiation of left from right In the normal condition, situs solitus, the right (R) lung is trilobed, the left (L) bilobed, the apex of the heart points to the left, the spleen and stomach are on the left, the liver is on the right and the small bowel loops in a counter-clockwise direction In situs inversus there is complete mirror-imaging, but usually no disease symptoms Situs ambiguous involves randomization of the arrangement of heart, lung, liver, spleen and stomach about the midline and is often associated with congenital heart defects Mirror image bilateral symmetry of the whole body is called isomerism, that of individual organs heterotaxia, and both are associated with a variety of pathologies The first observable sign of L/R asymmetry is looping of the heart tube to the right and the first relevant molecular signal detectable is of sonic hedgehog (Shh) protein from the notochord Cilia at the primitive node, powered by the motor protein dynein, then cause asymmetrical flow of perinodal fluid, which activates the genes for Nodal protein and Lefty-2 (LEFTB), specifically on the left side of the embryo Both are members of the transforming growth factor-β (TGF-β) family of signalling proteins and Nodal is responsible for the rightward looping of the heart tube These initiate signalling pathways that activate left-hand-specific transcription factors, including Pitx2 and eHAND, which promotes differentiation of the left ventricle, while dHAND promotes differentiation of the right ventricle Lefty-1 (LEFTA) prevents leakage of signals across the midline Situs inversus, isomerism and heterotaxia are produced by mutations in LEFTA, LEFTB and NODAL, while Kartagener syndrome involves random situs and other problems due to immotile cilia Mutations in the zinc finger proteins, ZIC3 and GLI3 (see Chapter 22), cause rare abnormalities of asymmetry including Greig cephalopolysyndactyly and Pallister–Hall syndrome Discrepancies in L/R asymmetry in MZ and conjoined twins indicate normal diffusion of lateralizing influence from the left, the twin arising on the R most commonly showing randomization Dorso-ventral differentiation Bone morphogenetic protein-4 (BMP-4) is emitted by the primitive node and induces ventral characteristics, but on its dorsal side proteins noggin and chordin are also expressed and these bind directly to BMP-4 and prevent it activating its receptor dorsally Sonic hedgehog (Shh) protein expressed in the notochord is responsible for dorsoventral patterning of the neural tube Mutations and duplications of SHH can cause holoprosencephaly (non-division of the forebrain) and cyclopia (a single, central eye) The limbs The proximo-distal axis The limb bud grows by proliferation of mesenchyme cells in the ‘progress zone’ less than a millimetre below the apical ectodermal ridge (AER) at its tip At this stage the mesenchyme cells receive progressively changing instructions mediated by fibroblast growth factors, FGF2, and 8, that define the extent of their proliferation, depending on which bony elements they are to form Limb abnormalities are a feature of Apert syndrome, in which there are mutations in the FGF2 receptor (FGFR2) Expression of p63 is crucial for sustaining the AER, and p63 mutations cause split hands and feet, called ectrodactyly The antero-posterior axis At the posterior margin of the limb bud is the ZPA, or zone of proliferating activity, the source of morphogens that define the form, number and location of the digits These diffuse anteriorly and generate a nested, overlapping pattern of HoxD and HoxA expression Mutations of HOXD13 cause synpolydactyly (fusion of the middle digits) Defects in the anterior and posterior elements of the upper limbs occur in Holt–Oram and ulnar–mammary syndromes, caused by mutations in TBX5 and TBX3 specifying thumb and little finger respectively Body patterning  Embryology and congenital abnormalities  109 43 Figure 43.1 Sexual differentiation Sexual differentiation of gonads and genital ducts Primordial germ cells Transverse section through embryo at 5–6 weeks Mesonephric duct Mesonephric duct Paramesonephric duct Indifferent Genital gonad ridge Mesonephric ducts regress under action of oestrogen Mesentery Paramesonephric duct Coelomic epithelium Primitive sex cords Gut months Primary ooctyes surrounded by follicle cells months Seminiferous tubule Mesonephric duct Mesonephric duct Paramesonephric ducts develop under action of oestrogen Mesonephric ducts develop under action of testosterone from Leydig cells Ovary Seminal vesicle Uterine tube Gubernaculum contracts under action of testosterone from Leydig cells Gubernaculum Vagina Vas deferens Testis Uterus Cervix Mature female system Female development Figure 43.2 Paramesonephric ducts regress under action of MIS from Sertoli cells Epididymis Scrotum Descended testicle in late fetus Male development Sexual differentiation of external genitalia Urethra Prepuce Glans Genital tubercle Clitoris Urethra Vestibule Labioscrotal swelling Labia majora Perineum Anus Action of oestrogen Female Medical Genetics at a Glance, Third Edition Dorian J Pritchard and Bruce R Korf 110  © 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd Penis Urogenital sinus Urogenital fold Labia minora Vagina Line of fusion of urethral folds Action of dihydrotestosterone Scrotum Perineum Testicle Anus Male Overview Sexual differentiation is initiated at fertilization, depending on whether the sperm carries an X or a Y chromosome At the blastocyst stage in XX embryos, one X chromosome in every cell is permanently inactivated, otherwise development of the sexes is similar until the SRY gene on the Y chromosome is activated and certain structures, including the brain, become progressively masculinized X chromosome inactivation At the late blastocyst stage cells inactivate all but one of their X chromosomes The nuclei of normal XX female cells therefore come to contain one inactive X, which can be seen at interphase as a Barr body in addition to their active X Presence or absence of a Barr body is the basis of the original Olympic sex test (now long since supplanted; see Chapter 11) The choice of whether it is the paternal or maternal X which becomes inactive is random in each somatic cell, but in descendent cells it remains the same Every woman therefore develops as a mosaic with respect to expression of her two X chromosomes In the extraembryonic trophoblast cells the paternal X is preferentially inactivated In oogonia the inactive chromosome is reactivated Genes in the pairing (pseudo-autosomal) region and several other sites on the X are not subject to inactivation, accounting for the variety of abnormalities of XXY and XO individuals (see Chapter 37) Early development At the beginning of week 5, up to 2000 primordial germ cells migrate from the endoderm cells of the yolk sac and infiltrate the primitive sex cords within the mesodermal genital ridges, which are developments of the coelomic epithelium The paired indifferent gonad is identical in males and females The ovary In the early ovary the primitive sex cords break down, but the surface epithelium proliferates and gives rise to the cortical cords, which split into clusters, each surrounding one or more germ cells The latter, now called oogonia, proliferate then enter meiosis as primary oocytes The testis The SRY gene carried only on the Y chromosome is expressed in week in the cells of the primitive sex cords Its product is a zinc finger transcription factor that binds to DNA in those same cells, leading to a masculine gene expression pattern These cells proliferate into the testis cords Leydig cells derived from the original mesenchyme of the gonadal ridge move in around the 8th week and until weeks 17–18 synthesize male sex hormones, or androgens, including testosterone, which initiate sexual differentiation of the genital ducts and external genitalia By the 4th month the male gonads also contain Sertoli cells derived from the surface epithelium of the gonad (see Chapter 44) Genital ducts Initially both sexes have two pairs of genital ducts: mesonephric (or Wolffian) and paramesonephric (or Mullerian) In females the mesonephric ducts regress under the action of oestrogens produced by the maternal system, placenta and fetal ovaries, but the parames- onephric ducts remain and become the uterine tubes and uterus (see Chapter 44) In males the Sertoli cells produce Mullerian inhibiting substance (MIS), which causes the paramesonephric ducts to degenerate Testosterone binds to an intracellular receptor protein and the hormone–receptor complex then binds to specific control sites in the DNA and regulates transcription of tissue-specific genes In male embryos testosterone converts the mesonephric ducts into the vas deferens, seminal vesicle and epididymis External genitalia The external genitalia are derived from a complex of mesodermal tissue located around the urogenital sinus At the end of the 6th week in both sexes this consists of the genital tubercle anteriorly, the paired urogenital folds on either side and lateral to these the labioscrotal swellings In females oestrogen stimulates slight elongation of the genital tubercle to form the clitoris, while the urogenital folds remain separate as the labia minora The urogenital sinus remains open as the vestibule and the labioscrotal swellings become the labia majora The tissues around the urogenital sinus synthesize 5-α-reductase, which in males converts testosterone secreted by the Leydig cells to dihydrotestosterone Under the action of this hormone the genital tubercle elongates into the penis, pulling the urethral folds forward to form the lateral walls of the urethral groove At the end of the 3rd month the tops of the walls fuse to create the penile urethra, while the urogenital sinus becomes the prostate (see Chapter 44) Descent of the testis Usually in the 7th month the testes descend from the peritoneal cavity between the peritoneal epithelium and pubic bones and into the scrotum This is mediated finally by the gubernaculum contracting under the influence of testosterone, but descent may not be completed until birth Puberty Puberty is triggered by hormones secreted by the pituitary gland acting on ovaries, testes and adrenal glands In girls, usually between ages 10 and 14 years, the ovaries respond by secreting oestrogen that stimulates breast growth About a year later menstruation commences, accompanied by maturation of the uterus and vagina and broadening of the pelvis Testosterone synthesis is stimulated in the adrenal glands and is responsible for growth of pubic and axillary hair in girls Menstruation ceases at menopause, at around 50 years In boys, starting at about 11–12 years, the testes enlarge and synthesis of androgens is reactivated The testis cords acquire a lumen, so forming the seminiferous tubules, which link up with the urethra The androgens enhance growth of the penis and larynx and initiate spermatogenesis Medical issues Disorders of sexual differentiation are dealt with in Chapter 44 Failure of testicular descent is called cryptorchidism Tumours arising from primordial germ cells are known as teratomas; they can contain several well-differentiated tissues (e.g hair, bone, sebaceous gland, thyroid tissue) and are usually benign (see Chapter 55) Sexual differentiation  Embryology and congenital abnormalities  111 44 Abnormalities of sex determination Figure 44.1 Summary of main events in sex determination Figure 44.3 Modified from Emery, Turnpenny and Ellard, 2005 Appearance of infants with campomelic dysplasia Indifferent gonad Medulla Cortex XX XY TDF production Paramesonephric (Müllerian) ducts Ovary OESTRADIOL Inhibition Promotion Mesonephric (Wolffian) ducts Inhibition Testis (Sertoli cells) (Leydig cells) MIS TESTOSTERONE Promotion Absence of 12th rib ANDROGEN RECEPTOR DIHYDROPROTEIN TESTOSTERONE Femoral and tibial malformation Promotion Internal female genitalia External female genitalia External male genitalia Internal male genitalia Fallopian tubes Uterus Proximal vagina Clitoris Labia Distal vagina Penis Scrotum Epididymis Seminal vesicles Vas deferens MIS: Müllerian inhibitor substance Figure 44.2 SRY: Sex determining region of the Y chromosome Genetic errors of steroidogenesis in the adrenal cortex Errors at steps 1-6 cause virilization of 46, XX females and hyper-virilization of 46, XY males Errors at steps and reduce normal virilization Cholesterol Pregnenolone 17-α hydroxypregnenolone Progesterone CAH Skeletal abnormalities in neck, under-developed shoulder blades, scoliosis 21-hydroxylase Deoxycorticosterone ALDOSTERONE 17-α hydroxyprogesterone Hip dislocation Dehydroepiandrosterone (DHEA) Androstenedione Oestrone CAH 21-hydroxylase TESTOSTERONE OESTRADIOL 11-deoxycortisol 5α-reductase ANDROGEN DIHYDROCORTISOL RECEPTOR TESTOSTERONE PROTEIN Promotion Internal male genitalia Ambiguous genitalia in 46, XY individuals 8, TFM Promotion External male genitalia Promotion External female genitalia Medical Genetics at a Glance, Third Edition Dorian J Pritchard and Bruce R Korf 112  © 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd Legs short, with dimples Abnormally rotated feet Overview Problems in genetic males Sexual differentiation begins in the early ‘indifferent’ gonads with secretion of oestrogen or androgen, depending on whether the Y-chromosome is absent or present Male conversion is mediated by the testis determining factor (TDF), a DNA-binding protein that is the product of the sex determining region (SRY) on the Y chromosome Subsequently steroidogenesis is triggered in the adrenal cortex and this becomes responsible for much of later sexual differentiation and maturation The roles and interactions of the hormones in normal sexual development are summarized in Figure 44.1 Figure 44.2 illustrates the steps in the relevant biochemical pathways at which pathogenic disruption most frequently occurs Disorders of sexual differentiation have been divided into five categories: congenital development of ambiguous genitalia – e.g virilization of a 46,XX individual by exposure to androgens, due to congenital adrenal hyperplasia; congenital disjunction of internal and external sexual anatomy – e.g female external anatomy in a 46,XY individual with testes, due to androgen insensitivity; incomplete development of sexual anatomy – e.g failure of gonadal development; sex chromosome anomalies – e.g Turner or Klinefelter syndrome (see Chapter 37); disorders of gonadal development – e.g individuals with an ovary on one side and a testis on the other, or a mixture of ovarian and testicular tissue Swyer syndrome individuals have a 46,XY karyotype, but a normal female phenotype due to the inheritance of a Y chromosome that lacks the SRY region, this being replaced with the corresponding sequence from the end of the X chromosome Androgen insensitivity syndrome (testicular feminization, or TFM) allows development of female external genitalia in XY individuals due to lack of the receptor for dihydrotestosterone (Figure 44.2 Step 8) Classically they present with a convincing external female phenotype, but lack of onset of menstrual periods, or inguinal hernia containing a testis, which can develop malignant cancer (gonadoblastoma) Males with deficiency in 5α-reductase, responsible for converting testosterone into dihydrotestosterone, may initially be classified as girls, but require reclassification at puberty when the deficiency is corrected by a surge of androgen from late-developing testes (Figure 44.2 Step 7) Other causes of ambiguous sexuality are Klinefelter syndrome (e.g 47,XXY; see Chapter 37) and 45,X/46,XY mosaicism due to loss of the Y from a progenitor cell during embryogenesis There can also be absence of the SRY gene from the Y chromosome due to previous illegitimate crossover between the X and Y One target of TDF is the SOX9 gene at 17q24, defects in this causing campomelic dysplasia, with bowing of the long bones, especially the tibia and femur, anomalies of ribs and vertebrae and frequently sex reversal from male to female phenotype (‘campomelic’ is derived from the Greek for ‘bent limb’) There are characteristic skin dimples over the bent bones, especially in the lower leg (Figure 44.3) The SOX9 gene codes for a transcription-regulating protein that recognizes the DNA sequence CCTTGAG It normally controls transcription of Type II collagen and proteoglycan during chondrocyte differentiation and with steroidogenic factor I regulates transcription of Muellerian inhibiting substance (Chapter 43) Its deficiency therefore leads to both skeletal malformations and defects in male sexual development Weakening of the cartilage of the upper respiratory tract can cause the larynx to collapse Problems in genetic females Virilization arising from defects at six or more steps in the biosynthesis of aldosterone and/or cortisol (hydrocortisone) creates ambiguous genitalia All are inherited as autosomal recessives By far the most significant is congenital adrenal hyperplasia (CAH, causing adrenogenital syndrome); due to 21-hydroxylase deficiency (21-OHD; Step in Figure 44.2) This so-called ‘classic OHD’ causes deficiency of aldosterone and cortisol and build-up of adrenocortical steroids proximal to the block, many of which have androgenic properties About 25% suffer excessive salt excretion and circulatory collapse at 2–3 weeks Reduced cortisol production stimulates adrenocorticotrophic hormone (ACTH) secretion and overgrowth of the adrenal glands An estimated 1% of the inhabitants of New York, of Jewish, Hispanic, Slavic and Italian origin, have ‘non-classic OHD’, with defects in one of five or so enzymes of related function (Figure 44.2 Steps 2–6) Other causes of ambiguous sexuality in females are maternal androgen ingestion and androgen-secreting tumours There can also be abnormal representation of the SRY gene on the X in an XX individual, due to illegitimate crossover between the X and Y in the father   Problems requiring immediate attention Difficulty with breathing Production of cholesterol is deficient in Smith–Lemli–Opitz syndrome and involves hypovirilization of boys (see Chapter 60) due to androgen deficiency, as cholesterol is a precursor of androgens Males with ‘non-classic OHD’ may have hypervirilization, with increased penis size Abnormalities of sex determination  Embryology and congenital abnormalities  113 Congenital abnormalities, pre-embryonic, embryonic and of intrinsic causation 45 Frequency of all birth defects Figure 45.1 Figure 45.2 Single defects Frequency of major congenital malformations in relation to development Figure 45.3 Relative frequency of birth defects in girls and boys Girls Boys Minor malformations 654 32 Major malformations 50 100 150/1000 Multiple defects Minor malformations 10–15 Frequency (%) Deformations Major malformations 10 Hip dislocation Talipes Cause of major congenital malformations Cleft palate year Hirschsprung disease 20 % 40 Organ-specific critical periods (see Chapter 41) Fertilization Gastrulation Birth First trimester = 'critical period' 60 Idiopathic Multifactorial Monogenic Chromosomal Maternal physiology Infection X-rays, drugs, alcohol Figure 45.6 Birth 15/100 Figure 45.5 Figure 45.4 Cleft lip and palate 2% Conception Deformations 345 Pyloric stenosis Gametes –2 Embryo Pre-embryo Fetus The Potter sequence Figure 45.7 Deficiency of amniotic fluid can arise as a consequence of kidney failure, urethral obstruction or leakage Reduced amnion volume can cause fetal compression with a range of consequences, including lethal failure of lung development Polycystic kidneys Type I Bilateral renal agenesis or 38 Causation of neural tube defects Normal pattern of neural tube closure in five waves Urethral obstruction Reduced urinary output or Chronic leakage of amniotic fluid Facial flattening (2) Talipes, hip dislocation Pulmonary hypoplasia Anencephaly Oligohydramnios Immobility Heart Central nervous system Eyes Ears Lips and midface Palate Teeth Limbs Genitalia Major structural abnormalities Minor or functional abnormalities or Second Third trimester trimester Breech presentation Death Medical Genetics at a Glance, Third Edition Dorian J Pritchard and Bruce R Korf 114  © 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd Failure of wave Spina bifida and meningomyelocele Failure of wave (5) Overview The word ‘congenital’ means ‘existing at birth’ and includes all ‘birth defects’ regardless of causation Congenital abnormalities are apparent in 1/40 newborn babies and account for 20–25% of infant deaths At birth 0.7% of babies have multiple major abnormalities, 2–3% a single major defect and 14% a single minor defect (Table 71.1) Probably 15–25% of congenital abnormalities have a recognized genetic, 10% an environmental and 20–25% a multifactorial basis Twinning accounts for 0.5–1.0% (see Chapter 53) and 40–60% are idiopathic, that is of unknown causation For medico-legal purposes malformations are regarded as ‘congenital’ only if recognized within the first weeks after birth Classification of defects Single abnormalities Malformations are due to errors occurring in the initial formation of structures, for example cleft lip with or without palate (CL  ±  P), polydactyly; most are multifactorial (see Chapters 50 and 51) Disruptions are due to disturbances after an organ has been formed, for example phocomelia resulting from a vascular problem Deformations are mechanical distortions, for example clubfoot (talipes) They frequently resolve completely soon after birth Dysplasias are abnormalities in tissue organization, for example in the differentiation of blood cells from vessels; most are monogenic Multiple abnormalities Sequences are cascades of effects, for example Pierre–Robin sequence, in which a primary defect in mandibular development produces secondary glossoptosis (drooping tongue) and cleft palate Syndromes are groups of anomalies that consistently occur together due to a single underlying cause, for example Down syndrome due to trisomy 21 Associations are where traits coincide more often than expected by chance The overall frequency of multiple malformations is 7/1000, apart from Down syndrome, the most frequently diagnosed being Beckwith– Wiedeman (see Chapter 27), DiGeorge and Williams–Beuren syndromes (Chapter 39), CHARGE syndrome (Chapter 40), Noonan syndrome and VATER association Noonan syndrome Frequency  1/2000 births Genetics  Defect in tyrosine phosphatase, non-receptor-type 11 (PTPN11) at 12q22 in most patients, other genes involved in the Ras signalling pathway (Chapter 54) mutated in others Features  Similar to Turner syndrome (Chapter 37), but affecting both sexes: short stature, neck webbing, increased carrying angle at the elbow, also learning difficulties, hypertelorism, down-slanting palpebral fissures, low-set ears and congenital heart disease Pulmonary stenosis is the most common heart lesion, but there are also aventricular (ASD) and ventricular septal defect (VSD) and hypertrophic cardiomyopathy (see below) Some have bleeding problems and a quarter have chest deformity CHARGE syndrome CHARGE involves the co-occurrence of Coloboma, Heart defects, choAnal atresia, Retarded growth, Genital abnormalities and abnormal Ears Mutation occur in either CHD7 or SEMA3E genes VATER/VACTERL association VATER involves Vertebral defects, Anal atresia, Tracheo-oEsophageal fistula (i.e abnormal fusion) and Renal defects VACTERL also includes Cardiac and Limb defects Timing and aetiology Pre-embryo Damage to the pre-embryo generally results in spontaneous abortion or regulative repair, so few errors in newborns are ascribable to preimplantation damage The following are exceptions: monozygotic twinning (see Chapter 53); germ layer defects, e.g ectodermal dysplasia affecting skin, nails, hair, teeth and stature Embryo The first trimester, especially between weeks and 8, is the critical period The palate and lips, eyes, ears, brain, neural tube and heart are all particularly susceptible at this stage and the CNS, eyes, lips and midface, teeth and genitalia remain especially vulnerable throughout gestation The following errors are most important during the first trimester: failure of cell migration, e.g neural crest cells, DiGeorge syndrome; failure of embryonic induction, e.g anophthalmia; failure of tube closure, e.g the neural tube defects (see Chapter 51); developmental arrest, e.g cleft lip (see Chapter 50); failure of tissue fusion, e.g cleft palate (see Chapter 51); defective morphogenetic fields, e.g sirenomelia; The foundations of consequent disturbances are laid at this stage, for example the Potter sequence The Potter/oligohydramnios sequence Babies are sometimes born with the combination of squashed facial features, severe talipes, dislocated hips, growth deficiency and lethal pulmonary hypoplasia Such babies typically adopted breech presentation The features arise from the ‘Potter sequence’, involving prolonged deficiency of amniotic fluid, called oligohydramnios Oligohydramnios develops due to defective urinary output by the baby, or chronic leakage This leads to fetal compression and immobility, with the consequences described The primary causes of reduced urinary output are bilateral renal agenesis (1/3000 births), polycystic kidney disease Type and obstruction of the urethra The recurrence risk for subsequent pregnancies is 1/33 Renal agenesis classes as a malformation, which through oligohydramnios causes secondary deformations, the combination constituting a syndrome and the series of events, a sequence Defects of the CNS Neural tube defects (NTDs) NTDs arise from failure of closure of the neural tube at the end of week (see Chapter 41) An anterior defect results in either anen­ cephaly or encephalocele (absence or protrusion of the brain) A posterior defect can lead to lumbosacral myelocele or meningomyel­ ocele (protruding spinal cord exposed, or covered by meninges), spina bifida and leg deformity (see Chapter 51) Holoprosencephaly Holoprosencephaly is failure of cleavage of the embryonic fore­ brain, resulting in severe mental impairment and abnormal facies, in Congenital abnormalities, pre-embryonic, embryonic and of intrinsic causation  Embryology and congenital abnormalities  115 phenotype: visible, tangible, or otherwise measurable properties of an organism resulting from the interaction of his or her genes with the environment pleiotropy: phenomenon of a single gene being responsible for a number of distinct and often seemingly unrelated phenotypic traits point mutation: substitution, insertion or deletion in DNA that involves only a small number of nucleotides polyadenylation: attachment of a ‘poly-A tail’ to an RNA transcript polygenic: resulting from the joint action of two or more genes polyhydramnios: excessive amniotic fluid polymorphism: presence in a population of two or more alleles at one locus at frequencies each greater than 1%; one allele of a polymorphic system, or its corresponding phenotype polypeptide: the first formed chain of amino acids created by transcription of mRNA, which when elaborated becomes a protein Potter sequence: a sequence of events that cause fetal abnormalities through oligohydramnios pre-embryo: the developing zygote from fertilization up to the end of week premutation: situation where there is expansion of triplet repeats beyond the normal range, but insufficient to cause disease preventive genetics: application of genetic insight for avoidance of disease proband: family member with specific phenotype who first came to the attention of the investigator or clinician progress zone: the region of the developing limb bud just behind the apical ectodermal ridge promutagen: a non-mutagenic substance that can be converted into a mutagen proposita: female proband propositus: male proband proto-oncogene: cellular oncogene; a normal allele that stimulates cell division, designated with the prefix ‘c’, e.g c-myc pseudoautosomal region: homologous regions of the X and Y chromosomes where pairing and crossover occurs ‘rare’: of genetic diseases, sometimes considered as occurring in less than 1/5000 births R bands: reverse bands, GC-rich parts of chromosomes that not stain darkly with Giemsa stain, c.f G bands recessive: an allele is said to be recessive to an alternative allele at the same locus when its expression is masked by that alternative in a heterozygote recurrence risk: risk a couple will have another child with the same disorder relapse: return of symptoms of disease after a period of apparent recovery remission: temporary abatement of symptoms of disease, literally ‘sending back’ repulsion: trans conformation restriction endonuclease: enzyme that specifically cuts doublestranded DNA at a defined base sequence restriction fragment: portion of double-stranded DNA released when DNA is cut with a restriction endonuclease reverse transcriptase: viral enzyme that creates DNA copies from an RNA template rickets: deficient ossification of bone epiphyses due to abnormality of calcium and phosphate metabolism related to vitamin D deficiency risk: the probability of occurrence of an event sarcoma: malignant tumour of mesodermal tissue second generation technology: see ‘next generation technology’ segmental aneuploidy: a chromosomal deletion of intermediate length sense strand: DNA strand complementary to the template strand and of sequence similar to that in the RNA transcribed sex chromosomes: X and Y chromosomes sex limitation: sex-related expression of an autosomal gene due to sex-related differences in anatomy or physiology sex linkage: inheritance and expression of an allele in relation to sex, by virtue of the gene being carried on a sex chromosome short tandem repeat: microsatellite sequence silencer: a sequence within the DNA that binds a transcription sup- pressor molecule silent mutation: mutation that causes no change in the corresponding polypeptide sister chromatids: two daughter strands of a duplicated chromosome joined by a common centromere somatic mutation: mutation that occurs in a body cell as distinct from the germ line SOX family: a family of gene transcription factors S phase: DNA synthetic phase of the cell cycle spindle: the tubulin fibre structure involved in separating newly formed chromosomes at mitosis SRY gene: a gene on the Y chromosome responsible for male differentiation START signal: triplet codon AUG that signifies where translation of mRNA should start statins: drugs that block cholesterol synthesis STOP signal: chain terminator, or ‘nonsense codon’; triplet codon that indicates where on the mRNA translation should stop: UAA, UAG, UGA structural gene: a gene that encodes the amino acid sequence of a protein, as distinct from a regulatory gene submetacentric: of a chromosome, with the centromere between the middle and one telomere susceptibility gene: gene with an allele that confers predisposition to a disease synapsis: side-by-side association of homologous chromosomes at meiosis syndrome: set of phenotypic features that occur together as a characteristic of a disease talipes: club foot tandem repeats: two or more copies of the same sequence of nucleotides arranged in direct succession in DNA TCA cycle: tricarboxylic acid cycle T cell: a lymphocyte generated in the thymus telomere: specialized end of a chromosome template strand: antisense strand; the DNA strand along which RNA polymerase runs, producing an RNA molecule of complementary sequence test mating: mating with a recessive homozygote which reveals the genotype of that individual threshold trait: a character that shows discontinuous variation considered to be superimposed upon a continuously variable distribution of liabilities trans conformation: alleles of two linked genes are said to be in trans conformation when they are on opposite chromosomes at meiosis, c.f cis Glossary  217 transcript: initially formed RNA product of the action of RNA polymerase translocation: mutation that involves transfer of a piece of DNA to wild type: naturally selected, theoretically with no significant overt an abnormal site trimester: one of the 3-month divisions of a gestation triplet repeat: tandem repetition of a group of three bases in DNA tumour suppressor gene: mitosis suppressor gene; a gene responsible for arresting mitosis at the G1 or G2 block viral oncogene: oncogene derived from a viral insert, designated with the prefix ‘v’, e.g v-myc Wright’s inbreeding coefficient: the probability that two alleles in a 218  Glossary abnormalities homozygote are identical by descent xanthoma: yellow skin discoloration due to subcutaneous cholesterol deposition zinc finger protein: a protein of specialized structure stabilized by an atom of zinc, with the property of binding to specific DNA sequences Appendix 1: the human karyotype The G-banded human karyotype (chromosomes are shown at the 550 band level of resolution) A B 14 D 15 16 10 11 12 19 13 C 17 E 18 Medical Genetics at a Glance, Third Edition Dorian J Pritchard and Bruce R Korf © 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd 21 F G 20 22 X Sex Y 219 Appendix 2: information sources and resources Introductory general textbooks Jorde, LB, Carey, JC and Bamshad, MJ Medical Genetics, 4th edn St Louis: Mosby, 2010 Korf, BR and Irons, MB Human Genetics and Genomics, 4th edn Oxford: Wiley-Blackwell, 2013 Nussbaum, RL, McInnes, RR and Willard, HF Thompson and Thompson’s Genetics in Medicine, 7th edn Philadelphia: Saunders, 2007 Sadler, TW Langman’s Medical Embryology, 12th edn Baltimore, Philadelphia: Lippincott Williams and Wilkins, 2011 Turnpenny, PD Emery’s Elements of Medical Genetics, 14th edn Edinburgh: Churchill Livingstone, 2012 Westman, JA Medical Genetics for the Modern Clinician Baltimore, Philadelphia: Lippincott Williams and Wilkins, 2005 Advanced and specialized texts and reviews Epstein, CJ, Erikson, RP and Wynshaw-Boris, A Inborn Errors of Development, 2nd edn Oxford: Oxford University Press, 2008 Harper, P Practical Genetic Counselling, 7th edn London: Arnold, 2010 Kinzler, KW and Vogelstein, B Lessons from hereditary colorectal cancer Cell, 87, 159–170, 1996 Lucasen, A, Parker, M Confidentiality and serious harm in genetics – preserving the confidentiality of one patient and preventing harm to relatives European Journal of Human Genetics 12, 93–97, 2004 Rantanen, E, Hietala, M, krisyofferson, U, Nippert, I, Schmidtke, J, Sequeiros, J and Kääriäinen, H What is ideal genetic counselling? A survey of current international guidelines European Journal of Human Genetics 16, 445–452, 2008 Rimoin, DL, Pyeritz, RE and Korf, BR Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th edn Oxford: Elsevier, 2013 Speicher, M, Antonarakis, SE and Motulsky, AG Human Genetics Problems and Approaches, 4th edn Berlin, Heidelberg, New York: Springer, 2010 Strachan, T and Read, A Human Molecular Genetics, 4th edn New York, Abingdon: Garland Science, 2011 Valle, D, Beaudet, AL, Vogelstein, B, Kinzler, KW Antonarakis, SE, and Ballabio, A Scriver’s Online Metabolic and Molecular Bases of Inherited Disease, vols 1–4, eds Scriver, CR and Sly, WS New York: McGraw-Hill, 2012 Young, ID Introduction to Risk Calculation in Genetic Counseling, 3rd edn Oxford: Oxford University Press, 2006 Internet sites American Society of Human Genetics (ASHG): www.ashg.org Website of major professional society dealing with research and education in genetics American College of Medical Genetics and Genomics (ACMG): www.acmg.net Website of US professional society dealing with medical genetics and genomics British Society for Human Genetics (BSHG): www.bshg.org.uk  A useful starting point with links to many other websites Clinical Genetics Computer Resources: www.kumc.edu/gec/prof/ genecomp.html  A valuable entry point to all the major genetics databases, for professional use Cold Spring Harbor DNA Learning Center: www.dnalc.org Educational materials related to DNA and genomics GeneCards: http://bioinfo.weizmann.ac.il/cards/  Database of human genes and their products GeneReviews: http://genereviews.org  An online genetics textbook with reviews and educational materials, including guidelines for diagnosis and management of genetic conditions and database of diagnostic laboratories HumGen: www.humgen.org Site with information on ethical and legal issues in human genetics Human Genome Epidemiology Network Reviews: www.cdc.gov/ genomics/gtesting/index.htm   Identifies human genetic variations and reports their frequency in different populations; describes associated disease risks and evaluates relevant genetic tests Human Mutation Database: www.hgmd.org  A compendium of databases of mutations responsible for human genetic disorders Infobiogen Database Catalogue (DBCAT): www.bio.net/bionet/ mm/arab-gen/1997-February/005413.html  A comprehensive public catalogue of biological databases National Center for Biotechnology Information: www.ncbi.nlm nih.gov/  Provides links to many valuable genetic resources National Organization for Rare Diseases (NORD): www.rarediseases org/  Maintains a list of rare diseases and affiliated groups Online Mendelian Inheritance in Man (OMIM): www.omim org  The standard and authoritative source of current knowledge of genes and single gene disorders Presents links to relevant literature, map locations and clinical summaries POSSUM: www.possum.net.au/  Computer-aided diagnosis of genetic disorders and syndromes PubMed: www.ncbi.nlm.nih.gov/pubmed  A service of the National Library of Medicine giving access to 11 million MEDLINE citations of standard publications on medical topics DNA-based techniques, gene mapping and gene therapy European Bioinformatics Institute (EBI): www.ebi.ac.uk/  Access to nucleotide and protein databases ENSEMBL: useast.ensembl.org Eukaryotic genome database HapMap: hapmap.ncbi.nlm.nih.gov Website for international HapMap project HUGO Genome Nomenclature: www.genenames.org Website for Human Genome Organization Nomenclature Committee Human Variome Project: www.humanvariomeproject.org Website for Human Variome Project National Human Genome Research Institute: www.genome.gov Website for NIH National Human Genome Research Institute Pharmacogenetics Knowledgebase: www.pharmgkb.org Information about pharmacogenetic polymorphisms RefSeq: www.ncbi.nlm.nih.gov/RefSeq/ Standardized database of genomic sequence UCSC Genome Browser: http://genome.ucsc.edu Website for major human genome browser Medical Genetics at a Glance, Third Edition Dorian J Pritchard and Bruce R Korf 220  © 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd University of Utah Genetic Science Learning Center: http://learn genetics.utah.edu Educational materials related to genetics US Surgeon General’s Family History Tool: www.hhs.gov/familyhistory/ Online tool for generating family pedigrees Embryology, development and birth defects Common disorders of infants: www.marchofdimes.org Images of normal and abnormal embryos: www.med.unc.edu/ embryo_images/ International Clearinghouse of Birth Defects: www.icbdsr.org/ page.asp?p=9895&l=1 Cancer General: http://cancer.gov Cancer Genome Atlas: http://cancergenome.nih.gov Laboratory services Clinical Molecular Genetics Society (UK): www.cmgs.org European Directory of DNA Laboratories: www.eddnal.com GeneClinics (USA): www.geneclinics.org GeneTests: www.genetests.org GeneReviews: www.genereviews.org DECIPHER: http://decipher.sanger.ac.uk Family support Family Village: www.familyvillage.wisc.edu/  Information on medical disorders, targeted at the general public Genetic Alliance (USA): www.geneticalliance.org  A good source of information on family support groups for genetic disorders Genetic Interest Group (UK): www.gig.org.uk  A national alliance of patient organizations NORD: see above Appendix 2: information sources and resources  221 Index Note: Page numbers in italics refer to figures Page numbers in bold refer to tables 1p36 deletion syndrome 103 16p11.2 deletion 211 17p13.3 microduplication 104–105 45S transcript, ribosomal RNA 63 47,XYY syndrome 95 abbreviations, listed 9–11, 90 abdominal wall defects 118 ABO blood groups 34, 77, 78, 79, 80, 175 abortion 188, 197 acetaldehyde dehydrogenase deficiencies 77 achondroplasia 22, 23 frequency 20 Gly380Arg mutation 67 overdominance 18 acidaemia and aciduria, amino acid catabolism disorder 155 acridine dyes 69 acrocentric chromosomes 90 acrodermatitis enteropathica 153 actin microfilaments 44, 45 acute intermittent porphyria 157–158 acylcarnitine, tandem mass spectrometry 165 adaptive immune system 169, 170, 171–172 adenomatous polyposis coli, familial 20, 142, 143 adenosine deaminase deficiency 26 see also severe combined immunodeficiency disease adhesion molecules see cell adhesion molecules adoption, babies from incestuous matings 29 adoption studies 130 adrenal cortex, steroidogenesis errors 112, 113 adrenoleukodystrophy, X-linked 163 adult-onset cerebellar ataxia 20 adult polycystic kidney disease 20, 24 advantage see heterozygote advantage affective disorders 134–135, 137 agammaglobulinaemia, X-linked 171–172 age-related mutation rates, spermatogenesis 68, 69 age-related penetrance, delayed onset 35 air travel, radiation exposure 69 Alagille syndrome 104, 105 albinism 79, 80 oculocutaneous 25–27, 30, 147, 148, 166 alcohol, teratogenesis 119, 125 alcohol dehydrogenase deficiencies 77 alcoholism 135 alkaptonuria 29, 146, 147 alleles 13, 17 frequency 79–81 allele-specific oligonucleotides messenger mistranslation 195 probes 176, 178, 183 α-1,4 and α-1,6 linkages, glucose moieties 160, 163 α1-antitrypsin deficiency 192 α-fetoprotein 189, 191, 191, 192 α-galactosidase deficiency 210 α-globin, mutations 67 5-α-reductase 111 deficiency 113 α-satellite DNA 55 α-thalassaemia 26, 67, 77, 192 Alu sequences, DNA 55, 67 Alzheimer disease 135, 209, 212 Amanita phalloides poisoning 61 amelogenin gene 36, 185 amino acids metabolism disorders 146–148, 155 succinogenic 154 aminoglycoside antibiotics 41, 195 5-aminolevulinate 157 2-amino-purine 69 ammonia 159 amniocentesis 190 amniotic fluid deficiency 114, 115 amplification HER2 144 proto-oncogenes 139 amplification refractory mutation system (ARMS) 182, 183 amputations, congenital 118 anaphase-promoting complex 51 anaphylactic shock 171 Anderson disease 164 androgen insensitivity syndrome 113 androgens, for hereditary angioneurotic oedema 196 anencephaly 114, 131, 189 aneuploidies 205 autosomal 92–93 segmental 99 sex chromosomes 94–95 aneurysms, Marfan syndrome 23 Angelman syndrome 18, 70, 71 angiogenesis, cancers 141 angioneurotic oedema, hereditary 171, 196 animal models 131 ankylosing spondylitis 174 Medical Genetics at a Glance, Third Edition Dorian J Pritchard and Bruce R Korf 222  © 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd antibiotics 65 aminoglycosides 41, 195 anticipation 73 anticodons 63 antiepileptic drugs 118, 125 antigen presentation, helper T cells 168, 169 antigen-presenting cells 169 anus, imperforate 116 aorta, Marfan syndrome 23 aortic valve atresia 122, 123 stenosis 122 Apert syndrome 22, 23, 109 ApoE locus 209, 212 apoptosis, resistance of cancers 140 arginosuccinic aciduria 159 array comparative genome hybridization 91, 144, 177, 178 arthrogryposis 118 A site, translation 65 association, genetic 82, 83, 88, 89 assortative mating 80 asthma 131 ataxia telangiectasia 69, 91, 143, 172 atopic diathesis 132, 137, 171 ATP7A (Cu transport protein) 153 atrial septa 120, 123 atrioventricular canal 121, 122, 123 Australian aborigines 77 autism 137 infantile 131, 132 autism spectrum disorder 210–211 autoimmune polyendocrinopathy syndrome 174 autoimmune regulator protein 173–174 autoimmunity 173, 174 autoradiography, dideoxynucleotide DNA sequencing 180 autosomal inheritance see dominant inheritance; recessive inheritance autosomes 18 background radiation 69 bacteria, human DNA libraries 86–87 bacterial inhibition assay 166 balanced translocations 97 Barr bodies 111 Barth syndrome 39 basal cell naevus syndrome 143 base analogues 69 base-excision repair, DNA 68, 69 base pair linkages 54, 55 Bayes’ theorem 42–43 bcr–abl fusion (Philadelphia chromosome) 98, 101, 144, 145, 208–209 Becker muscular dystrophy 39, 195, 207 Beckwith–Wiedemann syndrome 71, 72 belt desmosomes 45 β-globin 67, 77 β-oxidation degradative spiral 154 pathway 152, 154–155 β-thalassaemia 26, 67, 77 neonatal screening 192 splicing mutant 67 biochemistry 165–167 biotin 196 Blaschko’s lines 38, 39 blastocyst 107 sampling 191 blastomere sampling 191 blepharophimosis 126 blindness dominant, frequency 20 recessive 26, 30 blood groups 34, 77, 78, 79, 80, 175 blood transfusion 77, 78 Bloom syndrome 68, 69, 91, 143 B lymphocytes 169 body mass index 135 body patterning 108–109 bone marrow stem cells 168 bone morphogenetic protein-4 109 brachycephaly 126 brachydactyly 19 BRAF oncogene 144, 145 brain tumours, gene therapy 194 branched-chain amino acids 146, 148 branchial arches 108 BRCA genes 143, 208 breast cancer 208 DNA repair defect 68, 69, 143 prophylaxis 193 broad thumb–great toe syndrome 104 5-bromouracil 69 brother–sister matings 28, 29 Bruton agammaglobulinaemia 171–172 bulbus cordis 121 Burkitt lymphoma 96, 143 CAAT box 59 cadherins 141 café-au-lait spots 206 CAG trinucleotide repeat sequences, huntingtin gene 74 Cajal bodies 63 calpain 10 gene 134 campomelic dysplasia 112, 113 cancers 13, 138–145 DNA repair defects 68, 69, 143 familial 142–143, 208 genomics 144–145 predictive testing 192 prophylactic surgery 193 testing of children 199 therapies 194 candidate gene approach 85 carbamoyl phosphate synthetase deficiency 159 carbohydrate metabolism disorders 149–151 carbon atom numbering scheme, glucose 160 carcinogenesis 139 cardiomyocytes, embryonic 196 cardiomyopathy 134 carriers recessive conditions 27 X-linked inheritance 36–37 cascade screening 199 caspase 3, chronic myeloid leukaemia 195 cat eye syndrome 97 C-banding 90 CCR5 (T-cell surface receptor) 77, 172 CD45 (protein-tyrosine phosphatase receptor type C) 172 CDKN2A gene 50, 51 cDNA (complementary DNA) 83, 87, 145, 177 cell adhesion molecules 141 cell cycle 48–51 tumour suppressor proteins 139 cell junctions 45 cells 44–45 see also organelles cellular immune response 169 centiMorgan (unit) 83 central dogma 12 centric fusion 96, 97 centrioles 44, 45 centromeres 47, 55 centrosome cycle 49 centrosomes 45 cerebellar ataxias 20, 74 cerebral gigantism 100, 101 ceroid lipofuscinosis 26 Charcot–Marie–Tooth disease (HMSN) 20, 39, 45, 67 CHARGE syndrome 115 Chediak–Higashi syndrome 171 cheek brushing 209 chemicals mutagenesis 69 teratogenesis 118 children genetic testing 199 measurements 126 chimaerism, mosaicism vs 96 cholesterol 23–24 deficiency 113 chordin 109 chorionic villus sampling 190 chromatin 47, 59 chromosomal diseases, defined 13 chromosome 16p11.2 deletion 211 chromosome painting 91 chromosomes 46–47 analysis 90–91 cancers 145 flow sorting 84, 85 genomic imprinting 18, 71–72 inheritance via 17–18 structural abnormalities 96–101 see also aneuploidies; sex chromosomes chronic granulomatous disease 171 chronic myeloid leukaemia 143, 208–209 intrabodies 195 Philadelphia chromosome 98, 101, 144, 145, 208–209 citrullinaemia 159 classical galactosaemia 26 class switching 169 cleft lip 124, 125, 129, 131, 137 cleft palate 129, 130, 131, 137 clefts, face 125 cleidocranial dysplasia 74 clinical trials 212 clofibrate 45 cloning, DNA 85, 86–87 Cockayne syndrome 69 codominance 18, 34, 80 coefficient of kinship 29 coefficient of relationship 29 colchicine 45, 49 collagen, structure 65 colon cancer familial adenomatous polyposis coli 20, 142, 143 non-polyposis colon cancer 68, 69, 143 prophylaxis 193 colour blindness 38–39, 80 common atrium 122 common variable immunodeficiency 172 communication, genetic counselling 186–187 comparative genome hybridization (CGH) 91, 144, 177, 178 complement 169, 171 complementary DNA (cDNA) 83, 87, 145, 177 compound homozygosity, β-thalassaemia 67 concordance ratio 136 conditional probability 43 confidentiality 198 conflicts of interests 198–199 congenital abnormalities 114–119 congenital adrenal hyperplasia (CAH) 26, 113, 174, 175, 196 congenital dislocation of the hip 118, 131, 137 congenital erythropoietic porphyria 157, 158 congenital heart defects 116, 122–123, 131–132 conjoined twins 137 connexin 26 30 Index  223 conotruncal septum 121 consanguinity 14, 28–30, 80 consent cascade screening and 199 prenatal diagnosis 187 conservative mutations 67 consultands 15 contiguous-gene syndromes 97 WAGR syndrome 102, 143 continuous variation 128 copper, transport defects 153 coproporphyria, hereditary 157, 158 coproporphyrinogen III 157 copy number polymorphisms 76, 211 copy number variation 66, 67, 137, 185 cordocentesis 190 core sequences, DNA profiling 185 Cori disease 164 coronary artery disease 133–134, 137 correlation coefficient 128 corticosteroids see steroidogenesis cosmic rays 69 costs diseases 197 exome sequencing 211 counselling see genetic counselling coupling, alleles 82, 89 CpG sequences 59 methylation 71, 72 mutagenesis 69 creatine phosphokinase (CPK) 207 cri-du-chat syndrome 98, 99 critical period 115 Crohn disease 131 crossover 82–83, 84, 85 cross-reactivity, autoimmunity 174 Crouzon syndrome 22, 23 cryptorchidism 131 cyclin-dependent protein kinases 49, 50 cyclins 49, 50, 51 cyclopia 109 cyclosome inhibitor 51 cystathione synthase 148 cystic fibrosis 26, 31, 32, 212 allele frequency 80 carrier status 27, 210 consanguinity and 29 gene replacement 195 gentamicin 195 heterozygote advantage 32 modifier genes 35 neonatal screening 192 risk assessment 42, 43 cystic fibrosis transmembrane conductance regulator 31, 32 mutation 66, 67, 210 PCR 183 cystic hygroma, Turner syndrome 95 cystinuria 147, 148 cytochrome P450 enzymes 78 cytogenetics 13, 90–91 cytomegalovirus 118, 172 224  Index cytoplasm 45 cytoskeleton 45 deafness congenital 20, 27, 30 maternally transmitted ototoxic 41 debrisoquine hydroxylase deficiency 21, 78 decitabine 195 deep vein thrombosis 212–213 deformations 118 defined 115, 125 degree of penetrance 35 delayed onset, age-related penetrance 35 deleted in colorectal carcinoma gene 143 deletions 97, 99 see also microdeletions Δ32 allele, CCR5 77 dementia 133, 135 dentinogenesis imperfecta 20, 24 2′-deoxyribose 54, 55 desmosomes 45 deuteranomaly 38, 39 development, assessment 126 dexamethasone, congenital adrenal hyperplasia 196 dextrocardia 123 diabetes mellitus 137, 150, 151 maternal 118 relative risk (λs) 128 Type 132, 137, 150, 151 Type 133, 134, 137, 150, 151, 212 diallelic autosomal systems 79, 80 dictyotene state, oogenesis 53 dideoxynucleotide DNA sequencing 179, 180–181 DiGeorge anomaly 100, 172 TBX1 gene 109 dihydrobiopterin reductase 148 dihydrotestosterone 111 dimerization, pyrimidines 69 diphtheria toxin 65 diploidy 53, 92 direct repair, DNA 68, 69 direct-to-consumer testing, genomics 212 DIRVISH (fibre-FISH) 85 disruptions, defined 115, 125 diversion of metabolism 196 dizygotic twins 136 DNA 54–55 diagnostic techniques 166, 176–185, 209 fingerprinting 55, 184–185 libraries 86–87 mitochondrial 41, 45, 57 probes 177 profiling 55, 184–185 repair 68, 69, 143 replication 56–57 sexing 36 see also transcription DNA binding domains, transcription factors 61 DNA binding proteins 138, 139 DNA boost 185 DNA polymerases 57 dolichocephaly 126 dominant inheritance 16, 17, 18, 19–24, 34–35 allele frequency 80 DNA repair defects 143 linkage analysis 88–89 risk assessment 42, 43 X-linked 36, 37 DOPA oxidase 148 dot-blots 176, 178, 183 double helix, DNA 54, 55 double-minute chromatin bodies 139 Down syndrome 84, 92–93 empiric risk 43 familial 98 fetal screening 192 see also translocation Down syndrome drug metabolism, polymorphisms 78 drugs, teratogenesis 118, 119 Duchenne muscular dystrophy 38, 39, 207 female 101 polymerase chain reaction 182 risk assessment 42, 43 utrophin gene and 195 ductus arteriosus 122, 123 Duffy blood group 77 duodenal atresia 116 duplications, chromosomes 96, 97 dynamic mutation 18, 73–75 dysmorphology 124–125, 126 dysplasias, defined 115, 125 dystrophia myotonica protein kinase, gene 74, 75 dystrophin 39, 207 E2F (transcription promoter) 50, 51, 139 ears (external), measurements 126 ectoderm 107 ectopia lentis 23 ectrodactyly 35, 109 Edwards syndrome 92–93 EGF-R (epidermal growth factor receptor) 139 Ehlers–Danlos syndrome 20 elastin, Williams–Beuren syndrome 99–100 elliptocytosis 82 elongation gene transcription 61 translation 64, 65 elongation factors 65 embryogenesis 12, 106, 107 embryology 106–111 body patterning 108–109 congenital abnormalities 115 face 124–126 heart 109, 120–121 palate 125, 130 sexual 110–111 embryonic cardiomyocytes 196 embryonic disc 106, 107 embryonic stem cells 193 empiric risks 43, 128, 131 encephalocele 131 endocardial cushions 121, 122, 123 endocardial fibroelastosis 39 endocytosis 45 receptor-mediated 195 endoderm 107 endoplasmic reticulum 45 energy metabolism, cancers 141 enhancer sequences 59, 61, 67 environmental factors 13, 133, 192, 193, 195 enzyme assays 166 enzyme manipulation 196 lysosomal storage disorders 195, 210 enzymopathies 147 epicanthic folds 126 epidemiology 12 adult diseases 133–135 allele frequency 79–81 congenital abnormalities 114, 115 recessive conditions 28–29 epidermal growth factor receptor 139 epilepsy 131, 137 see also antiepileptic drugs epithelial–mesenchymal transition 141 ε4 allele 209, 212 erbB (epidermal growth factor receptor) 139 erythropoietic porphyrias 157 erythropoietic protoporphyria 157, 158 essential amino acids 147 ethics 197–199 direct-to-consumer testing 212 genetic counselling 187 prenatal diagnosis 188 ethnic groups autosomal disorders 76 DNA profiling 185 euchromatin 47 eugenics 197–198 exome sequencing 86, 87, 211 exons, splicing 60 exostoses see multiple exostoses expected date of delivery (EDD) 107 expressivity, variable 35 eyelids, deformations 126 Fabry disease 210 face 124–126 facio-scapulo-humeral dystrophy 20 factor V Leiden 213 factor VIII 38, 66 failure to thrive 126 familial adenomatous polyposis coli 20, 142, 143 familial cancers 142–143, 208 familial hypercholesterolaemia 20, 22, 23–24, 154 families, conflicts of interests 198–199 family linkage studies 85 family studies 130 family trees see pedigree diagrams Fanconi anaemia 69, 91, 143 fatty acids, catabolism disorders 154–155 favism 21 feminization, testicular 113 fertility, Klinefelter syndrome 94, 95 fertilization 106, 107 in vitro, preimplantation genetic diagnosis 190 fetal alcohol syndrome 119, 125 fetal circulation 122, 123 fetal haemoglobin, hereditary persistence 67 fetoscopy 190 fetus 107 congenital abnormalities arising in 117–119 stem-cell transplantation 196 trisomy, screening 192 fibre-FISH 85 fibrillin-1 23 fibroblast growth factor receptors 22, 23 fingerprinting, DNA 55, 184–185 first cousin marriages 28, 29 FISH (fluorescent in situ hybridization) 85, 90–91, 145, 205 flip inversion, haemophilia A 67 flow cytometry 84, 85 fluorescence, dideoxynucleotide DNA sequencing 180–181 fluorescence resonance energy transfer molecules 183 fluorescent in situ hybridization 85, 90–91, 145, 205 folic acid 131 foramen ovale 121, 123 forensic DNA techniques 184–185 fragile sites 96, 97 fragile X syndrome 39, 73, 74, 91, 178 frameshift mutations 66, 67 Friedreich ataxia 26, 74 fructose intolerance 150–151 fusion protein (BCR/abl) 98, 101, 144, 145, 208–209 G1 phase, cell cycle 49, 50 G1/S checkpoint 50–51 G2/M checkpoint 51 galactosaemia 150 classical 26 neonatal screening 192 galactose 149 GALT genotypes 149, 150 gametogenesis 52–53 gangliosides 161 see also Fabry disease gastroschisis 118 gastrulation 107 gatekeeper hypothesis 142 Gaucher disease 26, 161 enzyme replacement 195 G-bands, chromosomes 47, 90 GC boxes 59 gel electrophoresis 177 dideoxynucleotide DNA sequencing 180 pulsed field 178 gender selection 198 gene conversion, targeted 195 gene dosage 85 gene replacement 195 genes 12–13, 17, 58–59 body patterning 109 identification 86–87 length 59 gene therapy 12, 194–195 genetic code 64, 65 genetic counselling 186–187, 198, 199 genetic drift 80 genetic load 28 genetic registers 193 genital ducts 111 genitalia 110, 111 genome 55 genome-wide association studies 83 genomic imprinting 18, 70–72 genomic instability 139 genomics cancers 144–145 direct-to-consumer testing 212 see also molecular genetics; pharmacogenomics genotypes, defined 13 gentamicin 195 George III (king) 158 gestation 12–13 timing of congenital abnormalities 115 gestational diabetes mellitus 151 gigantism, cerebral 100, 101 Gilbert syndrome 61 globotriaosylceramide 210 glucose α-1,4 and α-1,6 linkages 160, 163 carbon atom numbering scheme 160 glucose 6-phosphate dehydrogenase deficiency allele frequency 80 environmental hazards 192 malaria and 76, 77 pharmacogenetics 21 glutaric acid 154 glutaryl-CoA dehydrogenase deficiency 155 Gly380Arg mutation, achondroplasia 67 Gly551Asp mutation 212 glycation, proteins 149, 151 glycogen 162 glycogen storage disorders 151, 163–164 glycolysis, cancers 141 glycosaminoglycans 161 glycosylation 65 GM2 gangliosidosis see Tay–Sachs disease Golgi complex 45 Index  225 gonadal mosaicism 43 Gorlin syndrome 143 Gower sign 38 gray (unit) 69 growth charts 124, 126 growth factor receptors 139 growth factors 138, 139 angiogenesis 141 cancers 140 growth hormone, for Prader–Willi syndrome 209 GTPases 139 Günther disease 157, 158 Guthrie test 166 haem 156, 157 haemochromatosis hereditary 153 primary 26, 174 haemoglobin 65 Haemoglobin Constant Spring 67 haemoglobinopathies 67 α-thalassaemia 26, 67, 77, 192 see also β-thalassaemia haemolytic disease of the newborn 77 haemophilia, gene therapy 195 haemophilia A 36, 38, 67 allele frequency 80 mutation 66 haemophilia B 67 halothane sensitivity 21 haploidy 53 haploinsufficiency 99 haplotypes 82, 175 Hardy–Weinberg law 80 Hayflick limit 140–141 HB11 (snoRNA species) 71 head, shape abnormalities 126 heart congenital defects 116, 122–123, 131–132 embryology 109, 120–121 Marfan syndrome 22, 23 heat maps 144 heavy chains, immunoglobulins 169 height (stature) 127 helix-loop-helices 61 helix-turn-helices 61 helper T cells, antigen presentation 168, 169 hemidesmosomes 45 hepatic coproporphyria 158 hepatic phosphorylase deficiency 164 hepatic porphyrias 157 hepcidin 153 HER2 144, 145 hereditary angioneurotic oedema 171, 196 hereditary coproporphyria 157, 158 hereditary motor and sensory neuropathy 20, 39, 45, 67 hereditary neuropathy with predisposition to pressure palsies 67 226  Index hereditary non-polyposis colon cancer 68, 69, 143 hereditary persistence of fetal haemoglobin 67 heritability 128, 137 heterochromatin 47, 59 heterogeneity, genetic 130 heterogeneous nuclear RNA (hnRNA) 61, 62 splicing mutant 67 heteroplasmy 41 heterosis 35 heterotaxia 109 heterozygosity 16 allele frequency 79, 80 autosomal recessive inheritance and 25, 27 dominant inheritance and 19, 34, 35 obligate 27 X chromosome inactivation 97 heterozygote advantage 32, 77 hexosaminidases 32 HFE gene 153 high-resolution gene mapping 85 hip, congenital dislocation 118, 131, 137 Hippocratic Oath 197 Hirschsprung disease 116 histones 47, 57 history, medical 15 HLA-associated diseases, empiric risk 43 HLA system 173, 174–175 diabetes mellitus 151 tissue transplantation 78 see also major histocompatibility complex holandric inheritance 37 holoprosencephaly 109, 115–116 Holt–Oram syndrome 109 homocystinuria 146, 147, 148 vitamin B6 for 196 homogeneously staining regions 139 homogentisic acid 147 homology, phenotypic 147 homoplasmy 41 homozygosity 16, 19 allele frequency 79, 80 autosomal recessive inheritance and 25, 27 compound, β-thalassaemia 67 housekeeping proteins 59 HOX genes 108, 109 human chorionic gonadotrophin 192 Human Genome Project 83, 199 human immunodeficiency virus 172 resistance to 77 human leucocyte antigen system see HLA system; major histocompatibility complex humoral immune response 169 Hunter syndrome 162, 163 Huntington disease 20, 35, 73–74, 182, 198–199 Hurler syndrome 162, 163 hybridization 177–178 whole genome sequencing 87 hybrid vigour 35 hydrocephalus 116 hydrops, Turner syndrome 95 21-hydroxylase deficiency (OHD) 113, 174, 175 hydroxymethylbilane 157 hydroxyurea 195 hyperargininaemia 159 hypercalcaemia, infantile 98, 99–100 hypercholesterolaemia, familial 20, 22, 23–24, 154 hyper-IgE syndrome 172 hyper-IgM syndrome 172 hypersensitivity 171 hypertelorism 126 hypertension 134, 137 hyperthermia malignant 21 pregnancy 119 hypophosphataemic rickets 39 hypospadias 131 hypotelorism 126 hypothyroidism, neonatal screening 192 hypoxanthine guanine phosphoribosyl transferase deficiency 159 I-cell disease 65, 147, 163 identification forensic 185 genes 86–87 imatinib 145, 195, 208 immune complexes 171 immune system 168–169 cancers, evasion 141 immunodeficiency 171, 172 see also severe combined immunodeficiency disease immunogenetics 13, 168–175 immunoglobulins 168, 169 imperforate anus 116 imprinting, genomic 18, 70–72 imprinting centres 71, 72 inborn errors of metabolism 13, 147, 166–167 inbreeding hybrid vigour 35 see also consanguinity inbreeding depression 28 incest 29 incidence, defined 81 incomplete dominance 35 incomplete penetrance 35, 42, 43 incontinentia pigmenti 38, 39 independent assortment, Mendelian 17 index cases 15 individualized medicine 12 infantile autism 131, 132 infantile hypercalcaemia 98, 99–100 infections, maternal 118 inflammatory microenvironments 139 information, genetic counselling 187 inhibin A 192 initiation gene transcription 61 translation 64, 65 innate immune system 168–169, 170, 171 insertional translocations 97 insulin 151 integrins 141 leucocyte adhesion deficiency 171 intelligence 134 intercalating agents 69 interferons see type interferon deficiency intermediate filaments 44, 45 interphase 48 interphase FISH 205 interpupillary distance, age vs 124 interstitial deletions 97 interventricular septum 121 intrabodies 195 intracytoplasmic sperm injection 187 introns 59 excision 60 in utero stem-cell transplantation 196 invasion, cancers 141 inversions, chromosomes 96, 97 flip inversion, haemophilia A 67 in vitro fertilization, preimplantation genetic diagnosis 190 iron overload 153 isochromosomes 96, 97 isolated cases, risk assessment 43 isomerism 109 iterative pyrosequencing 179, 181 ivacaftor 212 Janus kinase 172 Jervell–Lange–Nielsen syndrome 134 Job syndrome 172 joint probability 43 junctional complexes 44 Kabuki syndrome 211 kappa chains, immunoglobulins 169 Kartagener syndrome 109 karyotypes 92, 219 analysis 49, 90–91, 205 Kayser–Fleischer rings 153 Kearns–Sayre syndrome 41 Kelley–Seegmiller syndrome 159 kinetochores 47, 51, 55 kinky hair disease 153 Klinefelter syndrome 94–95 Krabbe disease 161 Kugelberg–Welander disease 33 lactose 149 tolerance 77, 150 lagging strands, DNA replication 57 lambda chains, immunoglobulins 169 Langer–Giedion syndrome 102 late onset, age-related penetrance 35 lateralization 109 leader sequences 59 leading strands, DNA replication 57 learning difficulties 29, 134 Leber hereditary optic neuropathy 41 Lefty-2 protein 109 Leigh disease 41 Lejeune syndrome 98, 99 leprosy 137 leptin 135 Lesch–Nyhan syndrome 157, 159 leucine zippers 61 leucocyte adhesion deficiency 171 Leydig cells 111 liability to disease 128 Li–Fraumeni syndrome 138, 143 limbs formation 108, 109 malformations 118, 126 linkage, genetic 13, 18, 82–83, 88–89, 131 see also family linkage studies lipid metabolism disorders 154–155 lipid storage disorders, lysosomal 160, 161 liposomes 195 lissencephaly 116 see also Miller–Dieker syndrome locus heterogeneity 27, 75 LOD scores 83 long-chain L-3-hydroxyacyl coA dehydrogenase deficiency (LCAD deficiency) 154, 155 long interspersed nuclear elements (LINES) 55 long non-coding RNA 62 long QT syndrome 134 losartan 23, 195 low-density lipoprotein receptor 23–24 luxury proteins 59 lysosomal storage disorders 160–164 enzyme assays 166 enzyme replacement 195, 210 lysosomes 45, 161 lysozymes 45, 161 macrocephaly 116, 126 macrophages 170 Madelung-like deformity 24 maintenance methylase 71, 72 major histocompatibility complex (MHC) 76, 168, 169, 173 malaria 76, 77 malformations, defined 115, 125 malignancy of tumours 141 see also cancers malignant hyperthermia 21 management of genetic disease 194–196 mandible, embryology 125 mannose phosphate 195 maple syrup urine disease 147, 148 mapping, genetic 83, 84–85, 87 Marfan syndrome 20, 22, 23, 195 Maroteaux–Lamy syndrome 163 massively parallel DNA sequencing 87, 181 mass spectrometry amplified DNA 183 see also tandem mass spectrometry mast cells 171 maternal blood, screening 189 maternally transmitted ototoxic deafness 41 maturity-onset diabetes of the young (MODY) 134, 150, 151 maxilla, embryology 125 McArdle disease 164 MDM2 protein 51 measles 137 measurements, children 126 medium chain acyl CoA dehydrogenase deficiency (MCAD deficiency) 26, 154, 155 medullary thyroid carcinoma 143 meiosis 52, 53 meiotic drive 18, 75 memory cells 169 Mendelian genetics 16–18 meningomyelocele 114, 131 Menkes disease 153 menstruation, X-ray safety measures 69 mental retardation 134 recessive 26, 29 mesenchyme 108 mesoderm 107 mesonephric ducts 111 messenger mistranslation 195 messenger RNA 60–61, 62 metabolites, detection 166 metacentric chromosomes 90 metal transport defects 153 metaphase I 53 metastasis, cancers 141 methionine synthase 148 methionyl tRNA 65 methylcytosine-guanine linkage 58 methylmalonic acidaemia 155, 166 vitamin B12 for 196 microarray studies 87, 205 comparative genome hybridization 91, 144, 145, 177, 178 pharmacogenomics 194 microcephaly 116, 126 microdeletions 91, 97 microfilaments 44, 45 microRNAs 63 microsatellite DNA 55, 184, 185 microtubules 44, 45 microvilli 45 Miller–Dieker syndrome 102, 116 minisatellite DNA 55, 184, 185 MIR sequences, DNA 55 mismatch repair, DNA 68, 69 missense mutations 66–67, 206 Index  227 mitochondria 44, 45 mitochondrial DNA 41, 45, 57 mitochondrial encephalopathy, lactic acidosis and stroke-like episodes 41 mitochondrial inheritance 18, 40–41 mitochondrion-specific RNA polymerase 41 mitosis 48, 49 MN blood groups 79, 80 mobile elements, frameshift mutations 67 modifier genes 35 molecular genetics 13 cancers 145 Mondini defect 30 monogenic diseases 13, 191 monosomy 92 Turner syndrome 95 monozygotic twins 136 Morquio syndrome 162, 163 mortality 12 twins 137 morula 107 mosaicism 96 gonadal 43 prenatal diagnosis 190 M-phase 48, 49 M-phase checkpoint 51 mucopolysaccharidoses (MPSs) 161–163 Mullerian ducts 111 Mullerian inhibiting substance 111 multifactorial diseases 127–135 defined 13 twin studies 136–137 multi-hit hypothesis 142, 143 multiple acetyl-CoA dehydrogenase deficiency 155 multiple births 136 multiple carboxylase deficiency, biotin 196 multiple endocrine neoplasia Type 143 multiple exostoses 20, 24 multiple sclerosis 137 multiplex amplifiable probe hybridization (MAPH) 183 multiplex PCR 183 muscular dystrophy see Becker muscular dystrophy; Duchenne muscular dystrophy muscular interventricular septum 121 mutagenesis 68–69, 192 mutations 13, 66–67 DNA sequencing 180 frequency estimation 21 neurofibromatosis Type I 206 nomenclature 67 see also dynamic mutation myoclonic epilepsy with ragged red fibre disease 41 myotonic dystrophy 20, 73, 74–75, 118 N-acetyl transferase deficiency 21 natural selection 81, 197 228  Index neonates cystic fibrosis diagnosis 32 diabetes 150, 151 immunity 169 screening 192 neoplasms see cancers neural crest cells 107, 108, 109 neural tube 107 defects 114, 115, 131 screening 191 pattern of closure 106 neurodegeneration, ataxia and retinitis pigmentosa 41 neurofibromatosis Type I 20, 35, 143, 206 neurofibromatosis Type II 143 neuronal apoptosis inhibitor protein, gene for 33 neutropenias 171 next generation DNA sequencing 87, 181 Niemann–Pick disease 161 nitrous acid 69 N-linked glycosylation 65 Nodal gene 109 noggin 109 nomenclature of mutations 67 non-allelic homologous recombination (NAHR) 99 non-coding RNA 62–63 non-histone chromosomal proteins (NHC proteins) 47 non-polyposis colon cancer 68, 69, 143 nonsense mutations 66, 67 Noonan syndrome 115 normal distribution 128 normal range 128 NOR staining 90 Northern blotting 178 nose, embryology 125 nuchal transparency 192 nuclear factor kappa B 174 nuclear matrix 45 nuclei 45 nucleolar organizer regions 63, 90 nucleolus 45 nucleosomes 47 nucleotide-excision repair, DNA 68, 69 nucleotides 55 obesity 135 obligate carriers 36 obligate heterozygosity 27 occupational screening 192 oculocutaneous albinism 25–27, 30, 147, 148, 166 oculocutaneous telangiectasia 172 odds ratios 133 oesophageal atresia 116 oestriol, unconjugated 192 Okazaki fragments 57 oligogenic diseases 130 oligohydramnios 114, 115 oligonucleotides, synthetic, whole genome sequencing 87 O-linked glycosylation 65 omphalocoele 118 oncogenes 138, 139, 142, 143 BRAF 144, 145 oogenesis 52, 53 opsonization 169 organelles 152 lysosomes 45, 161 ornithine cycle disorders 159 ornithine transcarbamylase deficiency 159 osteogenesis imperfecta 20 ostium primum 121, 122 ostium secundum 122 otosclerosis 20, 24 ototoxic deafness, maternally transmitted 41 ovaries cancers 208 development 111 overdominance 18, 35 overlapping genes 59 p16 (protein) 51 p21 (protein) 139 p53 (protein) 50, 51, 139 p63 gene, mutations 109 packing ratios, chromosomes 47 pair-wise concordance rate 136 palate cleft 129, 130, 131, 137 embryology 125, 130 paramesonephric ducts 111 parasitic twins 137 parent–child matings 28, 29 partial sex linkage 37 Patau syndrome 92–93 paternity, DNA profiling 184, 185 pattern baldness 37 Pearson syndrome 41 pedigree diagrams 14–15 autosomal recessive inheritance 25 Li–Fraumeni syndrome 138 Pendred syndrome 30 penetrance 18 incomplete 35, 42, 43 twin studies 136–137 peptidyl transferase reaction 64, 65 peroxisomal diseases 163 peroxisomes 45, 163 Pfeiffer syndrome 22, 23 phagocytosis 170 pharmacogenetics 12, 21 pharmacogenomics 194 pharyngeal arches 109 Phe508del mutation see cystic fibrosis transmembrane conductance regulator phenotypes, defined 13 phenotypic homology 147 phenylalanine metabolism 146 restriction 206 phenylketonuria 26, 33, 146, 147, 148, 205–206 carrier frequency 80 maternal 118 Schneidersitz 31 screening 165, 166, 192 phenytoin, sensitivity 78 Philadelphia chromosome 98, 101, 144, 145, 208–209 3′-5′ phosphodiester bonds 54 physical mapping 83, 84–85 Pierre–Robin sequence 115 pili torti 153 Pima Indians 133 plasma cells 169 plasmalemma 44, 45 pleiotropy 75, 147 PMP22 gene 67 pneumococcal infection, cystic fibrosis 192 Pol I (RNA polymerase I) 63 Pol II (RNA polymerase II) 59, 60, 62 Pol III (RNA polymerase III) 63 polar body sampling 191 polyadenylation sites, hnRNA 61 poly-A tail 61 polycystic kidney disease, adult 20, 24 polydactyly 118, 126 polygenic conditions 18, 127 polyglutamine tract diseases 74 polymerase chain reaction 182–183 blastomere sampling 191 chronic myeloid leukaemia 209 DNA profiling 184, 185 polymorphism 13, 76–78 association analysis 131 linkage analysis 88 polypeptides 65 polyribosomes 65 Pompe disease 164 population screening 191 population studies 130 porphobilinogen synthase deficiency 157 porphyria cutanea tarda 157, 158 porphyrias 156–159 porphyria variegata 21, 157, 158 positional cloning 85, 86, 87 posterior probability 43 postreceptor tyrosine kinases 139 post-replication repair, DNA 68, 69 post-translational modification 65 Potter sequence 114, 115 P protein 148 Prader–Willi syndrome 18, 63, 70, 71, 209 predictive genetics 12 predictive testing, cancers 192 pregnancy immune system 169 X-rays 189 see also gestation; prenatal diagnosis pregnancy-associated plasma protein A (PAPP-A) 192 preimplantation genetic diagnosis 190, 191 premature termination nonsense mutations 66, 67 prenatal diagnosis 187, 188–190 cystic fibrosis 32 Duchenne muscular dystrophy 207 inborn errors of metabolism 166 invasive procedures 189–190 neurofibromatosis Type I 206 screening 191–192 prevalence, defined 81 preventative genetics 191–193 primary constrictions, chromosomes 47 primed in situ hybridization 91 primers, polymerase chain reaction 183 primitive streak 107 prior probability 43 probands 15 probe patency of the oval foramen 123 profiling, DNA 55, 184–185 proflavine 69 promoters 59 prophase I, gametogenesis 53 prophylactic surgery 193 propionic acidaemia 155 prostate cancer 143 protanomaly 38, 39 proteins glycation 149, 151 modification 195 structure 65 synthesis 64–65 protein-tyrosine phosphatase receptor type C 172 proto-oncogenes 139 protoporphyrinogen IX 157 pseudoautosomal inheritance 37 pseudoautosomal region 36, 111 pseudocholinesterase deficiency 21 pseudodominance 27 pseudo-uridine sites, ribosomal RNA 63 P site, translation 65 psoriasis 137 puberty 111 pulmonary artery, atresia 122, 123 pulsed field gel electrophoresis 178 Punnett squares 16 purine nucleoside phosphorylase deficiency 157, 159 purines 55 metabolism disorders 157, 159 pyloric stenosis 118, 129, 131, 137 pyrimidines 55 dimerization 69 pyrosequencing, iterative 179, 181 quaternary structure, proteins 65 radiation mutagenesis 68, 69 occupational screening 192 teratogenesis 119 radon 69 raf protein 139 Ras signalling inhibitors 206–207 R-bands, chromosomes 47 Rb protein 50, 51, 139, 140 reading frames 64 real-time PCR 183 receptor-mediated endocytosis 195 recessive inheritance autosomal 16, 25–33 allele frequency 79, 80 DNA repair defects 143 inborn errors of metabolism 147 linkage analysis 88, 89 reciprocal translocations 97 risk assessment 42, 43 X-linked 36–37, 80 reciprocal translocations 97 recombinant DNA technologies 86–87 recurrence risks, multifactorial diseases 127, 128–129, 131 red and green colour blindness 38–39 regional mapping 85 registers, genetic 193 relative risk (λ) 128 release factors, in translation 65 religious perspective 198 renal agenesis 115, 131 replication, DNA 56–57 replication forks 56 reproductive genetic counselling 186–187, 198, 199 repulsion, alleles 82 restriction endonucleases 177 polymerase chain reaction 183 restriction fragment length polymorphism (RFLP) 177 restriction mapping 85 retinitis pigmentosa 26, 30 retinoblastoma (Rb) protein 50, 51, 139, 140 retinoblastomas 51, 142–143 Rett syndrome 39 reverse painting, chromosomes 91 Rhesus system 77, 82, 194 invasive procedures in pregnancy 190 rheumatoid arthritis 137 ribonucleotide reductase, inhibition 159 ribose 62 ribosomal RNA 63 ribosomes 63 ricin 65 rifampicin 61 ring chromosomes 96, 97 risk 81, 89 assessment 42–43 autosomal dominant inheritance 19–21 autosomal recessive inheritance 27 comparative 88 empiric 43, 128, 131 genetic counselling 186, 187 incestuous matings 29 X-linked inheritance 36–37 Index  229 RNA messenger RNA 60–61, 62 methionyl tRNA 65 mitochondrial 41 non-coding 62–63 Northern blotting 178 processing 61, 67 small nucleolar RNA 63, 71 RNA induced silencing complexes 195 RNA interference 195 RNA polymerase I 63 RNA polymerase II 59, 60, 62 RNA polymerase III 63 Robertsonian translocations 96, 97 Roberts syndrome 91 Romano–Ward syndrome 134 rubella 118 Rubinstein–Taybi syndrome 104, 105 Sandhoff disease 32 Sanfilippo syndrome 162, 163 sapropterin 206 satellite DNA 55 scaffold proteins, chromosomes 47 scaRNAs 63 schizophrenia 134, 135, 137 Schneidersitz 31 screening 191–193 ethics 198, 199 galactosaemia 150 maternal blood 189 phenylketonuria 165, 166, 192 see also prenatal diagnosis segmental aneuploidies 99 segregation, Mendelian 17 semiconservative replication 57 septa, cardiac 120, 121, 122, 123 sequences, defined 115, 125 sequence tagged sites (STSs) 83 sequencing, DNA 179–181 exome 86, 87, 211 massively parallel 87, 181 whole genome 86, 87 serine threonine kinases 139 severe combined immunodeficiency disease 157, 159, 172 gene replacement 195 see also adenosine deaminase deficiency sex chromosomes 17–18, 91 aneuploidies 94–95 sex influence 37 sexing, DNA samples 36 sex limitation 37 sex-related differential thresholds 127, 128–129 sex-related inheritance 17–18 Y-linked 37 see also X-linked inheritance sexual differentiation 110–111 abnormalities 112–113 230  Index Shields classification, dentinogenesis imperfecta 24 short interspersed nuclear elements (SINES) 55, 67 short tandem repeats (microsatellite DNA) 55, 184, 185 sibs, relative risk (λs) 128 sickle cell disease 26, 34–35, 77, 195 DNA hybridization techniques 176, 178 environmental hazards 192 geography 76 mutation 66 neonatal screening 192 signal recognition particle RNA 63 signal recognition particles 65 signal transduction cascade 138, 139 silencer sequences 59, 61, 67 silent mutations 66 single-locus probes, DNA profiling 185 single nucleotide polymorphisms, analysis 89 single-strand conformational polymorphism 183 singlet oxygen 157 sinus venosus 121 sister chromatids 47, 49 situs anomalies 109 skin colour, polymorphism 77 Sly syndrome 163 small interfering RNAs 195 small nuclear ribonucleoprotein (snRNP) 61, 63 small nuclear RNA (snRNA) 61, 62, 63 small nucleolar RNA (snoRNA) 63, 71 Smith–Lemli–Opitz syndrome 26, 113, 154 Smith–Magenis syndrome 100 smoking, maternal 119 SNURF-SNRPN sequence 71 snurps (snRNP) 61, 63 sodium benzoate 196 sodium valproate 118 somatic cell hybrids 85 somatic hypermutation 169 somites 107 sonic hedgehog protein 109 Sotos syndrome 100, 101 Southern blotting 176, 177–178, 185 spectrum, electromagnetic 68 spermatozoa formation 52, 53 function 107 intracytoplasmic injection 187 mutations 21, 68, 69 S-phase, cell cycle 48, 49 spherocytosis, hereditary 20 sphingolipidoses 161 spina bifida 114, 131, 137 spinal muscular atrophy 26, 31, 33 spliceosomes 61, 63 splicing mutants 67 SRY gene 37, 91, 111, 113 standard deviation (SD) 128 START signals 65 stature 127 stem cells bone marrow 168 cancers 141 embryonic 193 transplantation 196 steroidogenesis, adrenal cortex 112, 113 STOP signals 65, 195 stroke 134 substitutions (mutations) 66–67 succinogenic amino acids 154 sucrose 149 sulindac 193 surgery 196 prophylactic 193 survival motor neuron gene 33 Swyer syndrome 113 syncytiotrophoblast, biopsy 190 syndactyly 126 syndromes, defined 115 synpolydactyly 109 systemic lupus erythematosus 63 systems review 15 tailor’s posture 31 talipes equinovarus 118, 131, 137 tamoxifen 193 tandem mass spectrometry 165, 166–167 neonatal screening 192 Taq DNA polymerase 183 targeted gene conversion 195 TATA boxes 59, 61 taxol 49 Tay–Sachs disease 26, 32, 161 enzyme assay 166 mutation 66, 67 screening 192 TBX1 gene 109 T-cell receptors 168, 169 CCR5 77, 172 telangiectasia, oculocutaneous 172 telecanthus 126 telomerase 57, 141 telomeres 47, 55, 56, 57 template strands 57, 61 teratogenesis 69, 118–119, 125 teratomas 111 terminal deletions 97 termination gene transcription 61 translation 64, 65 termination of pregnancy 188, 197 tertiary structure, proteins 65 testes, development 111 testicular feminization 113 testis determining factor 113 test-matings 17 testosterone 111 tetrahydrobiopterin 205 tetralogy of Fallot 122, 123 thalassaemia α-thalassaemia 26, 67, 77, 192 see also β-thalassaemia thalassaemia major 67 thalidomide 119 thanatophoric dysplasia 22, 23 thiopurine methyltransferase deficiency 21 threshold traits, multifactorial 127, 128–129, 130 thrombospondin-1 141 thymus 173–174 thyroid cancer 143 tight junctions 45 T lymphocytes 168, 169 tolbutamide, sensitivity 78 tolerance, immune 173–174 Toll-like receptor deficiency 171 topoisomerase II 47 TORCH (organisms) 118 toxoplasmosis 118 trailer sequences 59 transcription factors 61 transcription (of genes) 60–61 transfer RNA 62, 63 transitions (mutations) 66 translation 64, 65 translocase reaction 65 translocation Down syndrome 100–101 translocations 97, 99 FISH 91 Robertsonian 96, 97 trisomy 21 92 unbalanced 205 X-autosome 101 transplantation organs/tissues 78, 174–175 stem cells 196 transposition of the great vessels 122, 123 transposons 55 mobile elements, frameshift mutations 67 transversions (mutations) 66 trastuzumab 145 triallelic autosomal systems 79, 80 trials, clinical 212 trichorhinophalangeal syndrome Type II 102 tricuspid atresia 122, 123 trimesters 13 triplet codons 65 triplet repeat sequences 66, 73, 74 triple-X syndrome 95 trisomy 92–93, 205 fetal screening 192 trisomy 21 92–93 phenotypic map 84 trophoblast 107 truncus arteriosus 121, 122, 123 tuberculosis 137 tuberous sclerosis 20 tumours see cancers tumour suppressor genes 138 tumour suppressor proteins 50–51, 139 Turner syndrome 94, 95 twins forensic identification 185 studies 130, 136–137 tissue compatibility 175 twin-to-twin transfusion syndrome 137 two-hit hypothesis 142–143, 206 type interferon deficiency 171 tyrosinaemia 147, 148 tyrosinase, oculocutaneous albinism 30 tyrosine, metabolism disorders 146 tyrosine kinases (postreceptor) 139 UBE3A gene 71 ubiquitin ligase 71 ulnar–mammary syndromes 109 ultrasound Down syndrome 192 prenatal diagnosis 189 ultraviolet light 69 unconjugated oestriol 192 unequal crossing over (mutation) 66 uniparental isodisomy 71, 209 unit inheritance 17 urea cycle disorders 159 uridine 62 urine signs, inborn errors of metabolism 166 urogenital sinus 111 utrophin gene 195 V600E mutation, BRAF oncogene 144, 145 VACTERL association 115 variable expressivity 35 variable number tandem repeats 185 variance 128, 137 vascular endothelial growth factor 141 VATER association 115 velocardiofacial syndrome 100 vemurafenib 144, 145 ventricular septal defects 122, 123 vinca alkaloids 45 virilization 112, 113 viruses carcinogenesis 139 effects on cell cycle 51 gene therapy 195 vitamin B6, for homocystinuria 196 vitamin B12 deficiency 148 for methylmalonic acidaemia 196 vitamin D 77 vitamin D-resistant rickets 39 VKORC1 (enzyme) 213 von Gierke disease 164 Von Hippel Lindau syndrome 20, 143 Von Recklinghausen disease (neurofibromatosis Type I) 20, 35, 143, 206 WAGR syndrome 102, 143 warfarin sensitivity 76, 78, 213 Werdnig–Hoffmann disease 33 whole genome sequencing 86, 87 Williams-Beuren syndrome 98, 99–100 Wilms tumour 143 Wilson disease 153 Wiskott–Aldrich syndrome 172 Wolffian ducts 111 Wolf-Hirschhorn syndrome 98, 99 women, X-ray safety measures 69 Wright’s inbreeding coefficient 29 X-autosome translocations 101 X chromosome 13, 17–18, 36 inactivation 96, 97, 111 Turner syndrome 95 xeroderma pigmentosum 91, 143 DNA repair defect 68, 69 X-linked adrenoleukodystrophy 163 X-linked agammaglobulinaemia 171–172 X-linked cardioskeletal myopathy 39 X-linked inheritance 36–39 allele frequency 80 genetic counselling and 187 linkage analysis 89 reciprocal translocations 97 risk assessment 42, 43 X-rays mutagenesis 69, 192 pregnancy 189 safety measures 69 Y chromosome 18, 36 Y-linked inheritance 37 Zellweger syndrome 26, 45, 163 zinc, acrodermatitis enteropathica 153 zinc-fingers 61, 109 zone of proliferating activity (ZPA) 109 UPLOADED BY [STORMRG] Index  231 ... Fronto-nasal process Maxillary process The mature palate Palatal shelves horizontal Primary palate Nasal septum Fused palatal plates Tongue The threshold model applied to creation of cleft palate... valvular stenosis Patent oval foramen Atresia of the aortic valves Stenosis of aortic valves Atrial septal defect Overriding aorta Valve leaflet (g) Pulmonary valvular atresia Patent oval foramen... upper jaw; and the central frontonasal prominence between the nasal placodes In the 5th week the latter invaginate, creating a ridge around each that constitute the lateral and medial nasal prominences