1. ¹Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
2. ²Divisão de Educação e Reabilitação de Distúrbios da Comunicação (DERDIC), Pontifícia Universidade Católica, São Paulo, Brazil

Correspondence: Dr K Lezirovitz, Departmento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, C.P. 11461, São Paulo, SP 05422-970, Brazil. Tel: +55 11 3091 7478; Fax: +55 11 3091 7478; E-mail: littlefelis@rocketmail.com

Received 11 April 2007; Revised 2 August 2007; Accepted 2 August 2007; Published online 12 September 2007.

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.