Family trio-based sequencing in 404 sporadic bilateral hearing loss patients discovers recessive and De novo genetic variants in multiple ways

Eur J Med Genet. 2021 Oct;64(10):104311. doi: 10.1016/j.ejmg.2021.104311. Epub 2021 Aug 17.


Hereditary hearing loss (HL) has high genetic and phenotypical heterogeneity including the overlapping and variable phenotypic features. For sporadic HL without a family history, it is more difficult to indicate the contribution of genetic factors to define a pattern of inheritance. We assessed the contribution of genetic variants and patterns of inheritance by a family trio-based sequencing and provided new insight into genetics. We conducted an analysis of data from unrelated sporadic patients with HL (n = 404) who underwent trio-based whole-exome sequencing (trio-WES) or proband-only WES (p-WES) or targeted exome sequencing (TES), and the samples of their unaffected-parents (n = 808)were validated. A molecular diagnosis was rendered for 191 of 404 sporadic HL patients (47.3%) in multiple modes of inheritance, including autosomal recessive (AR), autosomal dominant (AD) caused by de novo variants, copy-number variants (CNVs), X-linked recessive, and dual genetic diagnosis. Among these patients, 83 (43.5%) cases were diagnosed with variants in rare genes. Sporadic HL patients were identified by multiple modes of transmission. Observed variations in rare genes and multiple modes of inheritance can strikingly emphasize the important etiological contribution of recessive and de novo genetic variants to a large cohort of sporadic HL cases plus their parents.

Keywords: Copy-number variants; De novo variants; Dual genetic diagnosis; Exome sequencing; Sporadic hearing loss.

MeSH terms

  • Adolescent
  • Adult
  • DNA Copy Number Variations
  • Female
  • Gene Frequency
  • Genes, Dominant
  • Genes, Recessive*
  • Genetic Testing / methods
  • Genetic Testing / statistics & numerical data
  • Hearing Loss, Sensorineural / genetics*
  • Humans
  • Male
  • Mutation*
  • Pedigree