Abstract
Hearing loss (HL) is a common heterogeneous trait that involves variants in more than 200 genes. In this study, we utilized exome (ES) and genome sequencing (GS) to effectively identify the genetic cause of presumably non-syndromic HL in 322 families from South and West Asia and Latin America. Biallelic GJB2 variants were identified in 58 probands at the time of enrollment these probands were excluded. In addition, upon review of phenotypic findings, 38/322 probands were excluded based on syndromic findings at the time of ascertainment and no further evaluation was performed on those samples. We performed ES as a primary diagnostic tool on one or two affected individuals from 212/226 families. Via ES we detected a total of 78 variants in 30 genes and showed their co-segregation with HL in 71 affected families. Most of the variants were frameshift or missense and affected individuals were either homozygous or compound heterozygous in their respective families. We employed GS as a primary test on a subset of 14 families and a secondary tool on 22 families which were unsolved by ES. Although the cumulative detection rate of causal variants by ES and GS is 40% (89/226), GS alone has led to a molecular diagnosis in 7 of 14 families as the primary tool and 5 of 22 families as the secondary test. GS successfully identified variants present in deep intronic or complex regions not detectable by ES.
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Acknowledgements
We are grateful to the participating families included in this study. We thank all physicians, genetic counselors, and audiologists for providing all the relevant information. We are grateful to the DNA-Neurogenetics Bank of the Instituto Nacional de Ciencias Neurológicas for supporting the collection of DNA samples and associated data used in this publication. The content of this publication does not reflect the opinion of the DNA-Neurogenetics Bank. This work was supported by the NIH R01DC009645 grant to MT.
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Ramzan, M., Duman, D., Hendricks, L.C.P. et al. Genome sequencing identifies coding and non-coding variants for non-syndromic hearing loss. J Hum Genet 68, 657–669 (2023). https://doi.org/10.1038/s10038-023-01159-9
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DOI: https://doi.org/10.1038/s10038-023-01159-9
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