title: Estimation of the frequency of occult mutations for an autosomal recessive disease in the presence of genetic heterogeneity: application to genetic hearing loss disorders.
abstract: The routine testing for pathologic mutation(s) in a patient's DNA has become the foundation of modern molecular genetic diagnosis. It is especially valuable when the phenotype shows genetic heterogeneity, and its importance will grow as treatments become genotype specific. However, the technology of mutation detection is imperfect and mutations are often missed. This can be especially troublesome when dealing with a recessive disorder where the combination of genetic heterogeneity and missed mutation creates an imprecision in the genotypic assessment of individuals who do not appear to have the expected complement of two pathologic mutations. This article describes a statistical approach to the estimation of the likelihood of a genetic diagnosis under these conditions. In addition to providing a means of testing for missed mutations, it also provides a method of estimating and testing for the presence of genetic heterogeneity in the absence of linkage data. Gene frequencies as well as estimates of sensitivity and specificity can be obtained as well. The test is applied to GJB2 recessive nonsyndromic deafness, Usher syndrome types Ib and IIa, and Pendred-enlarged vestibular aqueduct syndrome.
authors.affiliation: Center for the Study and Treatment of Usher Syndrome, Boys Town National Research Hospital and the Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68131, USA. kimber@boystown.org
authors.forename: William J
authors.initials: WJ
authors.lastname: Kimberling
mesh_terms: D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods*; D004398:Dyneins / Q000235:genetics; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D034381:Hearing Loss / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D016013:Likelihood Functions; D009154:Mutation; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; C000631455:MYO7A protein, human; D000081412:Myosin VIIa; D000072259:Connexin 26; D009218:Myosins; D004398:Dyneins