Targeted Resequencing of Deafness Genes Reveals a Founder MYO15A Variant in Northeastern Brazil.

Identifying the genetic etiology in a person with hearing loss (HL) is challenging due to the extreme genetic heterogeneity in HL and the population-specific variability. In this study, after excluding GJB2 variants, targeted resequencing of 180 deafness-related genes revealed the causative variants in 11 of 19 (58%) Brazilian probands with autosomal recessive HL. Identified pathogenic variants were in MYO15A (10 families) and CLDN14 (one family). Remarkably, the MYO15A p.(Val1400Met) variant was identified in eight families from the city of Monte Santo in the northeast region of Brazil. Haplotype analysis of this variant was consistent with a single founder. No other cases with this variant were detected among 105 simplex cases from other cities of northeastern Brazil, suggesting that this variant is confined to a geographical region. This study suggests that it is feasible to develop population-specific screening for deafness variants once causative variants are identified in different geographical groups.

A community-based study of mucopolysaccharidosis type VI in Brazil: the influence of founder effect, endogamy and consanguinity.

Mucopolysaccharidosis type VI (MPS VI - Maroteaux-Lamy syndrome) is a globally rare lysosomal storage disease caused by a deficiency of arylsulfatase B. However, in Monte Santo, a poor and isolated rural region in Northeast Brazil with large family sizes and high rates of community endogamy and parental consanguinity (α = 0.00483), 9 living and 4 now deceased individuals in 11 kindreds have been diagnosed with MPS VI, all with the same p.H178L missense founder mutation. A further 33 deceased persons have been identified by family members as exhibiting the disease phenotype. Detailed pedigrees were constructed for the 13 genomically confirmed MPS VI patients, with blood samples collected from 236 unaffected family members to determine the prevalence of the p.H178L mutation. A total of 98 (20.8%) mutant alleles and 374 (79.2%) normal alleles were identified, with 41.5% of the individuals heterozygous for the p.H178L mutation and 58.5% homozygous for the normal allele. A significant number of other family members with a 50 or 25% chance of being heterozygous for the p.H178L mutation were unavailable for testing. The data indicate a compelling case for community-based neonatal screening in conjunction with further initiatives among MPS VI family members to promote genetic education and genetic counselling.

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

OBJECTIVE: There are many hearing impaired individuals in Monte Santo, a rural municipality in the state of Bahia, Brazil, including multiple familial cases strongly suggestive of a genetic aetiology. METHODS: The present study investigated 81 subjects with hearing impairment (HI) recruited from 36 families. Mutations often associated with HI, i.e. the DFNB1 mutations c.35delG in GJB2, deletions del(GJB6-D13S1830) and del(GJB6-D13S1854), and A1555G in the mitochondrial gene MTRNR1 were initially analyzed, with additional mutations in GJB2 identified by sequencing the coding region of the gene. RESULTS: Seven different mutations were present in GJB2 with mutations c.35delG and p.Arg75Gln, which are known to be pathogenic, identified in 37.0% of the subjects. Individuals homozygous for the c.35delG mutation were diagnosed in eight families, corresponding to 24.7% of unrelated individuals with nonsyndromic hearing impairment (NSHI), and an additional heterozygote for this mutation was present in a single family. Ten individuals (12.4%) in another family were heterozygous for the mutation p.Arg75Gln. CONCLUSIONS: Significant heterogeneity was observed in the alleles and patterns of NSHI inheritance among the subjects studied, probably due to the extensive inter-ethnic admixture that characterizes the peoples of Brazil, together with a high prevalence of community endogamy and consanguineous marriage.