Chapter 063. Chromosome Disorders (Part 10) Deletions involving the long arm of chromosome 22 (22q11) are the most common microdeletions identified to date, present in ~1/3000 newborns. VCF syndrome, the most commonly associated syndrome, consists of learning disabilities or mild mental retardation, palatal defects, a hypoplastic aloe nasi and long nose, and congenital heart defects (conotruncal defect). Some individuals with 22q11 deletion are more severely affected and present with DiGeorge syndrome, which involves abnormalities in the development of the third and fourth branchial arches leading to thymic hypoplasia, parathyroid hypoplasia, and conotruncal heart defects. In ~30% of these cases, a deletion at 22q11 can be detected with high-resolution banding; by combing conventional cytogenetics, FISH, and molecular detection techniques (i.e., Southern blotting or polymerase chain reaction analyses), these rates improve to >90%. Additional studies have demonstrated a surprisingly high frequency of 22q11 deletions in individuals with nonsyndromic conotruncal defects. Approximately 10% of individuals with a 22q11 deletion inherited it from a parent with a similar deletion. Smith-Magenis syndrome involves a microdeletion localized to the proximal region of the short arm of chromosome 17 (17p11.2). Affected individuals have mental retardation, dysmorphic facial features, delayed speech, peripheral neuropathy, and behavior abnormalities. Most of these deletions can be detected with cytogenetic analysis, although FISH is available to confirm these findings. In contrast, William syndrome, a chromosome 7 (7q11.23) microdeletion, cannot be diagnosed with standard or high-resolution analysis; it is only detectable utilizing FISH or other molecular methods. William syndrome involves a deletion of the elastin gene and is characterized by mental retardation, dysmorphic features, a gregarious personality, premature aging, and congenital heart disease (usually supravalvular aortic stenosis). In addition to microdeletion syndromes, there is now at least one well- described microduplication syndrome, Charcot-Marie-Tooth type 1A (CMT1A). This is a nerve conduction disease previously thought to be transmitted as a simple autosomal dominant disorder. Recent molecular studies have demonstrated that affected individuals are heterozygous for duplication of a small region of chromosome 17 (17p11.2–12). Although it is not yet clear why increased gene dosage would result in CMT1A, the inheritance pattern is explained by the fact that one-half of the offspring of affected individuals inherit the duplication- carrying chromosome. Imprinting Disorders Two other microdeletion syndromes, Prader-Willi syndrome (PWS) and Angelman syndrome (AS), exhibit parent-of-origin, or "imprinting," effects. For many years, it has been known that cytogenetically detectable deletions of chromosome 15 occur in a proportion of patients with PWS, as well as in those with AS. This seemed curious, as the clinical manifestations of the two syndromes are very dissimilar. PWS is characterized by obesity, hypogonadism, and mild to moderate mental retardation, whereas AS is associated with microcephaly, ataxic gait, seizures, inappropriate laughter, and severe mental retardation. New insight into the pathogenesis of these disorders has been provided by the recognition that parental origin of the deletion determines which phenotype ensues: if the deletion is paternal, the result is PWS, whereas if the deletion is maternal, the result is AS (Fig. 63-2). This scenario is complicated further by the recognition that not all individuals with PWS or AS carry the chromosome 15 deletion. For such individuals, the parental origin of the chromosome 15 region is again the important determinant. In PWS, for example, nondeletion patients invariably have two maternal and no paternal chromosomes 15 [maternal uniparental disomy (UPD)], whereas for some nondeletion AS patients the reverse is true (paternal UPD). This indicates that at least some genes on chromosome 15 are differently expressed, depending on which parent contributed the chromosome. Additionally, this means that normal fetal development requires the presence of one maternal and one paternal copy of chromosome 15. Approximately 70% of PWS cases are due to paternal deletions of 15q11- q13, whereas 25% are due to maternal UPD, and about 5% are caused by mutations in a chromosome 15 imprinting center. In AS, 75% of cases are due to maternal deletions, and only 2% are due to paternal UPD. The remaining cases are presumably caused by imprinting mutations (5%), or mutations in the UBE3A gene, which is associated with AS. The UPD cases are mostly caused by meiotic nondisjunction resulting in trisomy 15, subsequently followed by a normalizing mitotic nondisjunction event ("trisomy rescue") resulting in two normal chromosomes 15, both from the same parent. UBE3A is the only maternally imprinted gene known in the critical region of chromosome 15. However, several paternally imprinted genes, or expressed-sequence tags (ESTs), have been identified, including ZNF127, IPW, SNRPN, SNURF, PAR1, and PAR5. Chromosomal regions that behave in the manner observed in PWS and AS are said to be imprinted. This phenomenon is involved in differential expression of certain genes on different chromosomes. Chromosome 11 is one of these with an imprinted region, since it is known that a small proportion of individuals with the Beckwith-Wiedemann overgrowth syndrome have two paternal but no maternal copies of this chromosome. Acquired Chromosome Abnormalities in Cancer In addition to the constitutional cytogenetic chromosomal abnormalities that are present at birth, somatic chromosomal changes can be acquired later in life and are often associated with malignant conditions. As with constitutional abnormalities, somatic changes can include the net loss of chromosomal material (due to a deletion or loss of a chromosome), net gain of material (duplication or gain of a chromosome), and relocation of DNA sequences (translocation). Cytogenetic changes have been particularly well studied in (1) leukemias, e.g., Philadelphia chromosome translocation in CML [t(9;22)(q34.1;q11.2)]; and (2) lymphomas, e.g., translocations of MYC in Burkitt's [t(8;14)(q24;q32)]. These and other translocations are useful for diagnosis, classification, and prognosis. Analyses of cytogenetic changes are also useful in certain solid tumors. For example, a complex karyotype with Wilms' tumor, diploidy in medulloblastoma, and Her-2/neu amplification in breast cancer are poor prognostic signs. For detailed discussion of cancer genetics, see Chap. 79. Further Readings Dave BJ, Sanger WG: Role of cytogenetics and molecular cytogenetics in the diagnosis of genetic imbalances. Semin Pediatr Neurol 14(1):2, 2007 [PMID: 17331878] Jiang F, Katz RL: Use of interp hase fluorescence in situ hybridization as a powerful diagnostic tool in cytology. Diagn Mol Pathol 11:47, 2002 [PMID: 11854602] Lee C et al: Multicolor fluorescence in situ hybridization in clinical cytogenetic diagnostics. Curr Opin Pediatr 13:550, 2002 Menten B et al: Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: A new series of 140 patients and review of published reports. J Med Genet 43:625, 2006 [PMID: 16490798] Nasmyth K: Segregating sister genomes: The molecular biology of chromosome separation. Science 297:559, 2002 [PMID: 12142526] Rickman L et al: Prenatal detection of unbalanced chromosomal rearrangements by array CGH. J Med Genet 43: 353, 2006 [PMID: 16199537] Rimoin DL et al (eds): Emery and Rimoin's Principles and Practice of Medical Genetics , 4th ed. Philadelphia, Churchill Livingstone, 2001 Sharp AJ et al: Discovery of previously unidentified genomic disorders from the duplication architecture o f the human genome. Nat Genet 38:1038, 2006 [PMID: 16906162] . Chapter 063. Chromosome Disorders (Part 10) Deletions involving the long arm of chromosome 22 (22q11) are the most common microdeletions. one-half of the offspring of affected individuals inherit the duplication- carrying chromosome. Imprinting Disorders Two other microdeletion syndromes, Prader-Willi syndrome (PWS) and Angelman. recognition that not all individuals with PWS or AS carry the chromosome 15 deletion. For such individuals, the parental origin of the chromosome 15 region is again the important determinant. In