İranlı Ailelerin Tüm Ekzom Dizilemesi, Konjenital İşitme Kaybının Altında Yatan Yeni Varyantları Tanımlıyor

Özet (abstract)

Congenital nonsyndromic hearing loss (NSHL) is a highly genetically heterogeneous disorder involving more than 150 genes and numerous rare variants identified worldwide. In consanguineous populations such as Iran, recessive alleles are enriched, making genomic approaches particularly critical. Whole-exome sequencing (WES) has emerged as a powerful diagnostic tool, especially in cases where screening for prevalent etiologies, such as GJB2 mutations, yields negative results. In this context, the present study aimed to elucidate the genetic etiology of nonsyndromic hearing loss in consanguineous Iranian families and to assess the pathogenic relevance of identified novel variants via in silico analyses. Whole-exome sequencing identified pathogenic or likely pathogenic variants in four of the five families (80% diagnostic yield), affecting SLC26A4 , MYO7A , MYO15A , and PRPS1 . These comprised a recurrent, previously characterized SLC26A4 missense variant (c.1229 C > T, p.Thr410Met); a MYO7A exonic variant (c.2904G > T, p.Glu968Asp) predicted to disrupt splicing and newly associated here with an isolated, nonsyndromic phenotype; a previously reported MYO15A frameshift variant (c.5421del) for which segregation analysis provided the first evidence that it is sufficient, on its own, to cause hearing loss; and a novel PRPS1 missense variant (c.377 C > T, p.Thr126Ile). Computational predictions and structural modeling supported a deleterious effect for the MYO7A and PRPS1 variants, although these predictions await functional validation. The molecular etiology remained unresolved in one family. This study expands the mutational spectrum of hearing loss in Iran and demonstrates the diagnostic utility of WES in genetically heterogeneous, consanguineous populations. These findings support early diagnosis and genetic counseling and underscore the value of integrating splicing- and structure-based in silico analyses to prioritize novel variants for future functional validation.

Yazarların özeti; kaynağından alınmıştır. Human Genomics, 2026 · DOI ↗