Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

Abstract

Nonsyndromic autosomal recessive deafness accounts for 80% of hereditary deafness. To date, 52 loci responsible for autosomal recessive deafness have been mapped and 24 genes identified. Here, we report a large inbred Brazilian pedigree with 26 subjects affected by prelingual deafness. Given the extensive consanguinity found in this pedigree, the most probable pattern of inheritance is autosomal recessive. However, our linkage and mutational analysis revealed, instead of an expected homozygous mutation in a single gene, two different mutant alleles and a possible third undetected mutant allele in the MYO15A gene (DFNB3 locus), as well as evidence for other causes for deafness in the same pedigree. Among the 26 affected subjects, 15 were homozygous for the novel c.10573delA mutation in the MYO15A gene, 5 were compound heterozygous for the mutation c.10573delA and the novel deletion c.9957_9960delTGAC and one inherited only a single c.10573delA mutant allele, while the other one could not be identified. Given the extensive consanguinity of the pedigree, there might be at least one more deafness locus segregating to explain the condition in some of the subjects whose deafness is not clearly associated with MYO15A mutations, although overlooked environmental causes could not be ruled out. Our findings illustrate a high level of etiological heterogeneity for deafness in the family and highlight some of the pitfalls of genetic analysis of large genes in extended pedigrees, when homozygosity for a single mutant allele is expected.

Non-syndromic hearing impairment in a multi-ethnic population of Northeastern Brazil

“…The high frequency of homozygotes for the c.35delG mutation in Monte Santo can be ascribed to small effective population sizes and drift, and to parental consanguinity which was identified in 52.2% of the subjects analyzed, and was present in 55.0% of individuals with HI caused by the c.35delG mutation. However, as previously observed in a consanguineous Brazilian family [56], genetic heterogeneity was observed in familial cases of HI with an AR mode of inheritance, with the c.35delG mutation present in only some affected subjects (Figs. 2a, 2b).…”

A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss

“…Alternatively, there is a possibility of compound heterozygous mutations elsewhere in the genome which would not have been detected by our autozygosity mapping approach. Interestingly, a recent study unexpectedly detected multiple disease alleles at the DFNB3 locus within a single consanguineous pedigree [Lezirovitz et al, 2008]. The increasing use of exome sequence data now allows filtering for genetic variants that are compatible for multiple disease mechanisms and a recent study used this method to resolve a complex case of Miller syndrome to be a combination of two different genetic disorders [Ng et al, 2010].…”

Map of autosomal recessive genetic disorders in Saudi Arabia: Concepts and future directions

“…Similarly, three different mutations in ECM1 were described in three Saudi families with the rare disorder of lipoid proteinosis (generalized thickening of skin, mucosae, and certain viscera) . Of interest, allelic heterogeneity has been reported in the same consanguineous kindred from other populations as an exceptionally rare event [Lezirovitz et al, 2008;Benayoun et al, 2009].…”