Estimation of the frequency of occult mutations for an autosomal recessive disease in the presence of genetic heterogeneity: application to genetic hearing loss disorders

Hum Mutat. 2005 Nov;26(5):462-70. doi: 10.1002/humu.20221.


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.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Connexin 26
  • Connexins / genetics
  • DNA Mutational Analysis / methods*
  • Dyneins / genetics
  • Gene Frequency
  • Genetic Heterogeneity*
  • Genetic Linkage
  • Genetic Testing / methods*
  • Genotype
  • Hearing Loss / diagnosis*
  • Hearing Loss / genetics
  • Humans
  • Likelihood Functions
  • Mutation
  • Myosin VIIa
  • Myosins / genetics


  • Connexins
  • GJB2 protein, human
  • MYO7A protein, human
  • Myosin VIIa
  • Connexin 26
  • Myosins
  • Dyneins

Associated data

  • OMIM/276903