AUTHOR=Quaio Caio Robledo D’ Angioli Costa , Coelho Antonio Victor Campos , Moura Livia Maria Silva , Guedes Rafael Lucas Muniz , Chen Kelin , Ceroni Jose Ricardo Magliocco , Minillo Renata Moldenhauer , Caraciolo Marcel Pinheiro , Reis Rodrigo de Souza , Azevedo Bruna Mascaro Cordeiro de , Nobrega Maria Soares , Teixeira Anne Caroline Barbosa , Martinelli Lima Matheus , Mota Thamara Rayssa da , Matta Marina Cadena da , Colichio Gabriela Borges Cherulli , Roncalho Aline Lulho , Ferreira Ana Flavia Martinho , Campilongo Gabriela Pereira , Perrone Eduardo , Virmond Luiza do Amaral , Moreno Carolina Araujo , Prota Joana Rosa Marques , França Marina de , Cervato Murilo Castro , Almeida Tatiana Ferreira de , Oliveira Filho Joao Bosco de TITLE=Genomic study of nonsyndromic hearing loss in unaffected individuals: Frequency of pathogenic and likely pathogenic variants in a Brazilian cohort of 2,097 genomes JOURNAL=Frontiers in Genetics VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.921324 DOI=10.3389/fgene.2022.921324 ISSN=1664-8021 ABSTRACT=

Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy–Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4–15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.