Chapter 062. Principles of Human Genetics (Part 17)

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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...

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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, Phenotype Inheritance OMIM Protein LMNA, Emery– AD 181350 Lamin A/C Dreifuss muscular dystrophy (AD) Familial AD 151660 partial lipodystrophy Dunnigan Hutchinson- AD 176670 Gilford progeria Atypical AD 150330 Werner syndrome Dilated AD 115200 cardiomyopathy
Early-onset AD 607554 atrial fibrillation Emery– AR 604929 Dreifuss muscular dystrophy (AR) Limb-girdle AR 159001 muscular dystrophy type 1B Charcot- AR 605588 Marie-Tooth type 2B1 KRAS Noonan AD 163950 syndrome Cardio- AD 115150 facio-cutaneous
syndrome Locus Heterogeneity Phenotype Gene Chromosomal Protein Location Familial hypertrophic cardiomyopathy Genes MYH7 14q12 Myosin encoding heavy chain beta sarcomeric proteins TNNT2 1q2 Troponin-T2 TPM1 15q22.1 Tropomyosin alpha 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 Genes MTT1 Mitochondrial tRNA encoding isoleucine nonsarcomeric proteins MTTG Mitochondrial tRNA glycine PRKAG2 7q35-q36 AMP- activated protein kinase γ2 subunit DMPK 19q13.2-13.3 Myotonin protein kinase (myotonic dystrophy) FRDA 9q13 Frataxin (Friedreich ataxia) Polycystic PKD1 16p13.3-13.12 Polycystin 1
kidney disease (AD) PKD2 4q21.-23 Polycystin 2 (AD) PKHD1 6p21.1-p12 Fibrocystin (AR) Noonan PTPN11 12q24.1 Protein- syndrome tyrosine phosphatase 2c KRAS 12p12.1 KRAS Note: AD, autosomal dominant; AR, autosomal recessive