title: A recessive Mendelian model to predict carrier probabilities of DFNB1 for nonsyndromic deafness.
abstract: Mutations in the DFNB1 locus, where two connexin genes are located (GJB2 and GJB6), account for half of congenital cases of nonsyndromic autosomal recessive deafness. Because of the high frequency of DFNB1 gene mutations and the availability of genetic diagnostic tests involving these genes, they are the best candidates to develop a risk prediction model of being hearing impaired. People undergoing genetic counseling are normally interested in knowing the probability of having a hearing impaired child given his/her family history. To address this, a Mendelian model that predicts the probability of being a carrier of DFNB1 mutations, using family history of deafness, has been developed. This probability will be useful as additional information to decide whether or not a genetic test should be performed. This model incorporates Mendelian mode of inheritance, the age of onset of the disease, and the current age of hearing family members. The carrier probabilities are obtained using Bayes' theorem, in which mutation prevalence is used as the prior distribution. We have validated our model by using information from 305 families affected with congenital or progressive nonsyndromic deafness, in which genetic analysis of GJB2 and GJB6 had already been performed. This model works well, especially in homozygous carriers, showing a high discriminative power. This indicates that our proposed model can be useful in the context of clinical counseling of autosomal recessive disorders.
authors.affiliation: Genes and Disease Program, and CEGEN Barcelona Genotyping Mode, Center for Genomic Regulation, Barcelona, Spain. juanramon.gonzalez@crg.es
authors.forename: Juan R
authors.initials: JR
authors.lastname: González
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wang
authors.forename: Ester
authors.initials: E
authors.lastname: Ballana
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
mesh_terms: D000328:Adult; D001499:Bayes Theorem; D002675:Child, Preschool; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D003638:Deafness / Q000175:diagnosis / Q000235:genetics*; D005060:Europe; D005190:Family; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive / Q000502:physiology; D005820:Genetic Testing; D034381:Hearing Loss / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010375:Pedigree; D011336:Probability; D012372:ROC Curve
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26