Ans. c (Muscular dystrophies) (Ref. H - 18th/Ch. 63; 16th/pg. 360).Many disorders exhibit the feature of locus heterogeneityf which refers to the fact that mutations in different genes can cause phenotypicaily similar disorders. For example, osteogenesis imperfecta, long QT syndrome, muscular dystrophy, homocystinuria, retinitis pigmentosa, and hereditary predisposition to colon cancer or breast cancer can each be caused by mutations in distinct genes. In these cases, the choice of which genes to test is often determined by unique clinical and family history features, the relative prevalence of mutations in various genes, or test avail- ability.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 (3-globin locus can cause b-thalassemia.# 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; and3) 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.Phenotypic Heterogeneity# Phenotypic heterogeneity occurs when more than one phenotype is caused by allelic mutations (e.g., different mutations in the same gene).# For example, mutations in the myosin VIIIA gene can result in four distinct clinical disorders:1) Autosomal recessive deafness DFNB2,2) Autosomal dominant nonsyndromic deafness DFNA11,3) Usher IB syndrome (congenital deafness, retinitis pigmentosa) and4) An atypical variant of Usher's syndrome,# Similarly, identical mutations in the FGFR2 gene can result in very distinct phenotypes: Crouzon syndrome (craniofacial synostosis), or Pfeiffer syndrome (acrocephalopolysyndactyly).Locus or Nonallelic Heterogeneity and Phenocopies# Nonallelic or locus heterogeneity refers to the situation in which a similar disease phenotype results from mutations at different genetic loci.# This often occurs when more than one gene product produces different subunits of an interacting complex or when different genes are involved in the same genetic cascade or physiologic pathway.# For example, osteogenesis imperfecta can arise from mutations in two different procollagen genes (COL1A1 or COL1A2) that are located on different chromosomes. The effects of inactivating mutations in these two genes are similar because the protein products comprise different subunits of the helical collagen fiber.# Similarly, muscular dystrophy syndromes can be caused by mutations in various genes, consistent with the fact that it can be transmitted in an X-linked (Duchenne or Becker), autosomal dominant (limb-girdle muscular dystrophy type 1), or autosomal recessive (limb-girdle muscular dystrophy type 2) manner. Mutations in the X-linked DMD gene, which encodes dystrophin, are the most common cause of muscular dystrophy.# Recognition of nonallelic heterogeneity is important for several reasons: (1) the ability to identify disease loci in linkage studies is reduced by including patients with similar phenotypes but different genetic disorders; (2) genetic testing is more complex because several different genes need to be considered along with the possibility of different mutations in each of the candidate genes; and (3) novel information is gained about how genes or proteins interact, providing unique insights into molecular physiology.Genetic terms1.Locus heterogenicityMutations at different loci can produce the same phenotype (e.g., albinism)2.Variable expressionNature and severity of the phenotype varies from one individual to another.3.Incomplete penetranceNot all individuals with a mutant genotype show the mutant phenotype.4.PleiotrophyOne gene has > one effect on an individual's phenotype5.ImprintingDifferences in phenotype depend on whether the mutation is of maternal or paternal origin (e.g., Angelman's syndrome , Prader-Willi syndrome )6.AnticipationSeverity of disease worsens as age of onset of disease is earlier in succeeding generation (e.g., Huntington's disease)7.Loss of heterozygosityIf patient inherits or develops mutation in a tumor suppressor gene, complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes.8.Dominant negative mutationExerts a dominant effect. A heterozygote produces a nonfunctional altered protein that prevents the normal gene product from functioning.9.Linkage disequilibriumTendency for certain alleles at 2 linked loci to occur together often than expected by chance. Measured in a population, not in family; and often varies in different populations.10.MosaicismOccurs when cells have different genetic makeup (e.g.Lyonization-random X-inactivation in females)