Further evidence for loss-of-function mutations in the CEACAM16 gene causing nonsyndromic autosomal recessive hearing loss in humans.

Mutations in the CEACAM6 gene were first described as causing autosomal dominant nonsyndromic hearing loss, but two splice-altering variants have been recently described as causing autosomal recessive nonsyndromic hearing loss. We describe the novel and extremely rare loss-of-function variant c.436 C > T/p.(Arg146Ter) in the CEACAM16 gene segregating with post-lingual progressive autosomal recessive hearing loss. This variant is predicted to significantly reduce the size of the wild type protein. Our results give additional support that loss-of-function variants in CEACAM16 cause autosomal recessive hearing loss in humans.

Genetic heterogeneity in autosomal recessive hearing loss: a survey of Brazilian families.

Introduction: Hearing loss is a frequent sensory impairment type in humans, with about 50% of prelingual cases being attributed to genetic factors. Autosomal recessive hearing loss (ARHL) exhibits great locus heterogeneity and is responsible for 70%-80% of hereditary nonsyndromic cases. Methods: A total of 90 unrelated Brazilian individuals were selected for having hearing loss of presumably autosomal recessive inheritance, either born from consanguineous marriages or belonging to families with two or more affected individuals in the sibship and most cases were of normal hearing parents. In all cases, common pathogenic variants in GJB2 (c.35delG), GJB6 [del(GJB6-D13S1830) and del(GJB6-D13S1854)] and MT-RNR1 (m.1555A>G) were discarded and most were previously assessed by complete Sanger sequencing of GJB2. Their genetic material was analyzed through next-generation sequencing, targeting 99 hearing loss-related genes and/or whole exome sequencing. Results: In 32 of the 90 probands (36,7%) causative variants were identified, with autosomal recessive inheritance confirmed in all, except for two cases due to dominant variants (SIX1 and P2RX2). Thirty-nine different causative variants were found in 24 different known hearing loss-associated genes, among which 10 variants are novel, indicating wide genetic heterogeneity in the sample, after exclusion of common pathogenic variants. Despite the genetic heterogeneity, some genes showed greater contribution: GJB2, CDH23, MYO15A, OTOF, and USH2A. Conclusion: The present results confirmed that next-generation sequencing is an effective tool for identifying causative variants in autosomal recessive hearing loss. To our knowledge, this is the first report of next-generation sequencing being applied to a large cohort of pedigrees with presumable autosomal recessive hearing loss in Brazil and South America.

Frequency and origin of the c.2090T>G p.(Leu697Trp) MYO3A variant associated with autosomal dominant hearing loss.

We recently described a novel missense variant [c.2090T>G:p.(Leu697Trp)] in the MYO3A gene, found in two Brazilian families with late-onset autosomal dominant nonsyndromic hearing loss (ADNSHL). Since then, with the objective of evaluating its contribution to ADNSHL in Brazil, the variant was screened in additional 101 pedigrees with probable ADNSHL without conclusive molecular diagnosis. The variant was found in three additional families, explaining 3/101 (~3%) of cases with ADNSHL in our Brazilian pedigree collection. In order to identify the origin of the variant, 21 individuals from the five families were genotyped with a high-density SNP array (~600 K SNPs- Axiom Human Origins; ThermoFisher). The identity by descent (IBD) approach revealed that many pairs of individuals from the different families have a kinship coefficient equivalent to that of second cousins, and all share a minimum haplotype of ~607 kb which includes the c.2090T>G variant suggesting it probably arose in a common ancestor. We inferred that the mutation occurred in a chromosomal segment of European ancestry and the time since the most common ancestor was estimated in 1100 years (CI = 775-1425). This variant was also reported in a Dutch family, which shares a 87,121 bp haplotype with the Brazilian samples, suggesting that Dutch colonists may have brought it to Northeastern Brazil in the 17th century. Therefore, the present study opens new avenues to investigate this variant not only in Brazilians but also in European families with ADNSHL.

Characterization of a novel MYO3A missense mutation associated with a dominant form of late onset hearing loss.

Whole-exome sequencing of samples from affected members of two unrelated families with late-onset non-syndromic hearing loss revealed a novel mutation (c.2090 T > G; NM_017433) in MYO3A. The mutation was confirmed in 36 affected individuals, showing autosomal dominant inheritance. The mutation alters a single residue (L697W or p.Leu697Trp) in the motor domain of the stereocilia protein MYO3A, leading to a reduction in ATPase activity, motility, and an increase in actin affinity. MYO3A-L697W showed reduced filopodial actin protrusion initiation in COS7 cells, and a predominant tipward accumulation at filopodia and stereocilia when coexpressed with wild-type MYO3A and espin-1, an actin-regulatory MYO3A cargo. The combined higher actin affinity and duty ratio of the mutant myosin cause increased retention time at stereocilia tips, resulting in the displacement of the wild-type MYO3A protein, which may impact cargo transport, stereocilia length, and mechanotransduction. The dominant negative effect of the altered myosin function explains the dominant inheritance of deafness.

Multiprofessional committee on auditory health: COMUSA.

Created in 2007, COMUSA is a multiprofessional committee comprising speech therapy, otology, otorhinolaryngology and pediatrics with the aim of debating and countersigning auditory health actions for neonatal, lactating, preschool and school children, adolescents, adults and elderly persons. COMUSA includes representatives of the Brazilian Audiology Academy (Academia Brasileira de Audiologia or ABA), the Brazilian Otorhinolaryngology and Cervicofacial Surgery Association (Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico Facial or ABORL), the Brazilian Phonoaudiology Society (Sociedade Brasileira de Fonoaudiologia or SBFa), the Brazilian Otology Society (Sociedade Brasileira de Otologia or SBO), and the Brazilian Pediatrics Society (Sociedade Brasileira de Pediatria or SBP).

Comitê multiprofissional em saúde auditiva: COMUSA / Multiprofessional committee on auditory health: COMUSA

Criado em 2007, o COMUSA é um comitê multiprofissional que agrega áreas de estudo da Fonoaudiologia, Otologia, Otorrinolaringologia e Pediatria e tem como objetivo discutir e referendar ações voltadas à saúde auditiva de neonatos, lactentes, pré-escolares e escolares, adolescentes, adultos e idosos. Fazem parte do COMUSA representantes da Academia Brasileira de Audiologia (ABA), Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico Facial (ABORL), Sociedade Brasileira de Fonoaudiologia (SBFa), Sociedade Brasileira de Otologia (SBO) e Sociedade Brasileira de Pediatria (SBP).

Created in 2007, COMUSA is a multiprofessional committee comprising speech therapy, otology, otorhinolaryngology and pediatrics with the aim of debating and countersigning auditory health actions for neonatal, lactating, preschool and school children, adolescents, adults and elderly persons. COMUSA includes representatives of the Brazilian Audiology Academy (Academia Brasileira de Audiologia or ABA), the Brazilian Otorhinolaryngology and Cervicofacial Surgery Association (Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico Facial or ABORL), the Brazilian Phonoaudiology Society (Sociedade Brasileira de Fonoaudiologia or SBFa), the Brazilian Otology Society (Sociedade Brasileira de Otologia or SBO), and the Brazilian Pediatrics Society (Sociedade Brasileira de Pediatria or SBP).