Estimation of the frequency of occult mutations for an autosomal recessive disease in the presence of genetic heterogeneity

Application to genetic hearing loss disorders

William J Kimberling

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)462-470
Number of pages9
JournalHuman mutation
Volume26
Issue number5
DOIs
StatePublished - Nov 1 2005

Fingerprint

Hearing Disorders
Genetic Heterogeneity
Mutation Rate
Hearing Loss
Mutation
Information Storage and Retrieval
Gene Frequency
Molecular Biology
Genotype
Technology
Phenotype
Sensitivity and Specificity
DNA

Keywords

  • GJB6
  • Gene frequency
  • MYO7A
  • Mutation detection
  • Non-syndromic deafness
  • PDS
  • Pendred syndrome
  • Sensitivity
  • Specificity
  • USH2A
  • Usher syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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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.",
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