Abstract
We studied a family presenting 10 individuals affected by autosomal dominant deafness in all frequencies and three individuals affected by high frequency hearing loss. Genomic scanning using the 50k Affymetrix microarray technology yielded a Lod Score of 2.1 in chromosome 14 and a Lod Score of 1.9 in chromosome 22. Mapping refinement using microsatellites placed the chromosome 14 candidate region between markers D14S288 and D14S276 (8.85 cM) and the chromosome 22 near marker D22S283. Exome sequencing identified two candidate variants to explain hearing loss in chromosome 14 [PTGDR – c.G894A:p.R298R and PTGER2 – c.T247G:p.C83G], and one in chromosome 22 [MYH9, c.G2114A:p.R705H]. Pedigree segregation analysis allowed exclusion of the PTGDR and PTGER2 variants as the cause of deafness. However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype. This gene has been previously described as mutated in autosomal dominant hereditary hearing loss and corresponds to DFNA17. The mutation identified in our study is the same described in the prior report. Thus, although linkage studies suggested a candidate gene in chromosome 14, we concluded that the mutation in chromosome 22 better explains the hearing loss phenotype in the Brazilian family.
Highlights
According to the World Health Organization (WHO) almost 360 million people of all ages around the world have disabling hearing loss
DFNA9 is located at chromosomal region 14:31,343,740-31,359,821 and it was mapped by Manolis et al (1996)
Robertson et al (1998) studied three different families affected by autosomal dominant hearing loss which mapped to DFNA9, and they found the COCH gene to be associated with hearing loss
Summary
According to the World Health Organization (WHO) almost 360 million people of all ages around the world have disabling hearing loss. Hearing loss can be caused by environmental factors, by genetic factors, or both. Hereditary hearing loss exhibits enormous heterogeneity of inheritance mechanisms, of chromosomal loci and of alleles in the same locus. Almost 70% of hereditary hearing loss cases do not display syndromic features (Keats and Berlin, 1999) and are called nonsyndromic. About 80% of nonsyndromic hereditary hearing loss is due to autosomal recessive mechanisms (The Connexin Deafness Homepage), the autosomal dominant mechanism corresponds to 10-20% (Guilford et al, 1994), X-linked inheritance corresponds to 2-3% of the genetic cases of hearing loss (Van Camp et al, 1997) and the contribution of maternal inheritance was estimated to be near 1%. About 170 loci have been mapped for nonsyndromic hearing loss and different types of mutations in 75 identified genes have been found in humans (http://hereditaryhearingloss.org/). Regarding autosomal dominant hearing loss, about 55 loci have been mapped and 29 genes have been identified
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