Chapter 062. Principles of Human Genetics (Part 17) Genotypes describe the specific alleles at a particular locus. For example, there are three common alleles (E2, E3, E4) of the apolipoprotein E (APOE) gene. The genotype of an individual can therefore be described as APOE3/4 or APOE4/4 or any other variant. These designations indicate which alleles are present on the two chromosomes in the APOE gene at locus 19q13.2. In other cases, the genotype might be assigned arbitrary numbers (e.g., 1/2) or letters (e.g., B/b) to distinguish different alleles. A haplotype refers to a group of alleles that are closely linked together at a genomic locus (Fig. 62-8). Haplotypes are useful for tracking the transmission of genomic segments within families and for detecting evidence of genetic recombination, if the crossover event occurs between the alleles (Fig. 62-3). As an example, various alleles at the histocompatibility locus antigen (HLA) on chromosome 6p are used to establish haplotypes associated with certain disease states. For example, 21-hydroxylase deficiency, complement deficiency, and hemochromatosis are each associated with specific HLA haplotypes. It is now recognized that these genes lie in close vicinity to the HLA locus, which explains why HLA associations were identified even before the disease genes were cloned and localized. In other cases, specific HLA associations with diseases such as ankylosing spondylitis (HLA-B27) or type 1 diabetes mellitus (HLA-DR4) reflect the role of specific HLA allelic variants in susceptibility to these autoimmune diseases. The recent characterization of common SNP haplotypes in four populations from different parts of the world through the HapMap project is providing a novel tool for association studies designed to detect genes involved in the pathogenesis of complex disorders (Table 62-1). The presence or absence of certain haplotypes may also become relevant for the customized choice of medical therapies (pharmacogenomics) or for preventative strategies. Allelic Heterogeneity Allelic heterogeneity refers to the fact that different mutations in the same genetic locus can cause an identical or similar phenotype. For example, many different mutations of the β-globin locus can cause β-thalassemia (Table 62-4) (Fig. 62-4). In essence, allelic heterogeneity reflects the fact that many different mutations are capable of altering protein structure and function. For this reason, maps of inactivating mutations in genes usually show a near-random distribution. Exceptions include: (1) a founder effect, in which a particular mutation that does not affect reproductive capacity can be traced to a single individual; (2) "hot spots" for mutations, in which the nature of the DNA sequence predisposes to a recurring mutation; and (3) localization of mutations to certain domains that are particularly critical for protein function. Allelic heterogeneity creates a practical problem for genetic testing because one must often examine the entire genetic locus for mutations, as these can differ in each patient. For example, there are >1400 reported mutations in the CFTR gene (Fig. 62-7). The mutational analysis initially focuses on a panel of mutations that are particularly frequent (often taking the ethnic background of the patient into account), but a negative result does not exclude the presence of a mutation elsewhere in the gene. One should also be aware that mutational analyses generally focus on the coding region of a gene without considering regulatory and intronic regions. Because disease-causing mutations may be located outside the coding regions, negative results should be interpreted with caution. Table 62-4 Selected Examples of Locus Heterogeneity and Phenotypic Heterogeneity Phenotypic Heterogeneity Gene, Protein Phenotype Inheritance OMIM Emery– Dreifuss muscular dystrophy (AD) AD 181350 Familial partial lipodystrophy Dunnigan AD 151660 Hutchinson- Gilford progeria AD 176670 Atypical Werner syndrome AD 150330 LMNA, Lamin A/C Dilated cardiomyopathy AD 115200 Early-onset atrial fibrillation AD 607554 Emery– Dreifuss muscular dystrophy (AR) AR 604929 Limb-girdle muscular dystrophy type 1B AR 159001 Charcot- Marie- Tooth type 2B1 AR 605588 Noonan syndrome AD 163950 KRAS Cardio- facio-cutaneous AD 115150 syndrome Locus Heterogeneity Phenotype Gene Chromosomal Location Protein Familial hypertrophic cardiomyopathy MYH7 14q12 Myosin heavy chain beta TNNT2 1q2 Troponin-T2 TPM1 15q22.1 Tropomyosin alpha Genes encoding sarcomeric proteins MYBPC3 11p11q Myosin binding protein C TNNI3 19q13.4 Troponin 1 MYL2 12q23-24.3 Myosin light chain 2 MYL3 3p Myosin light chain 3 TTN 2q24.3 Cardiac titin ACTC 15q11 Cardiac alpha actin MYH6 14q1 Myosin heavy chain alpha MYLK2 20q13.3 Myosin light- peptide kinase CAV3 3p25 Caveolin 3 MTT1 Mitochondrial tRNA isoleucine MTTG Mitochondrial tRNA glycine PRKAG2 7q35-q36 AMP- activated protein kinase γ2 subunit DMPK 19q13.2-13.3 Myotonin protein kinase (myotonic dystrophy) Genes encoding nonsarcomeric proteins FRDA 9q13 Frataxin (Friedreich ataxia) Polycystic PKD1 16p13.3-13.12 Polycystin 1 (AD) PKD2 4q21 23 Polycystin 2 (AD) kidney disease PKHD1 6p21.1-p12 Fibrocystin (AR) PTPN11 12q24.1 Protein- tyrosine phosphatase 2c Noonan syndrome KRAS 12p12.1 KRAS Note: AD, autosomal dominant; AR, autosomal recessive . Chapter 062. Principles of Human Genetics (Part 17) Genotypes describe the specific alleles at a particular locus. For example, there are three common alleles (E2, E3, E4) of the. focuses on a panel of mutations that are particularly frequent (often taking the ethnic background of the patient into account), but a negative result does not exclude the presence of a mutation. involved in the pathogenesis of complex disorders (Table 62-1). The presence or absence of certain haplotypes may also become relevant for the customized choice of medical therapies (pharmacogenomics)