Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families

Abstract

Background. Approximately 70% of congenital deafness is attributable to genetic causes. Incidence of congenital deafness is known to be higher in families with consanguineous marriage. In this study, we investigated the genetic causes in three consanguineous Pakistani families segregating with prelingual, severe-to-profound deafness. Results. Through targeted next-generation sequencing of 414 genes known to be associated with deafness, homozygous variants c.536del (p. Leu180Serfs ∗ 20) in TECTA, c.3719 G>A (p. Arg1240Gln) in MYO7A, and c.482+1986_1988del in HGF were identified as the pathogenic causes of enrolled families. Interestingly, in one large consanguineous family, an additional c.706G>A (p. Glu236Lys) variant in the X-linked POU3F4 gene was also identified in multiple affected family members causing deafness. Genotype-phenotype cosegregation was confirmed in all participating family members by Sanger sequencing. Conclusions. Our results showed that the genetic causes of deafness are highly heterogeneous. Even within a single family, the affected members with apparently indistinguishable clinical phenotypes may have different pathogenic variants.

Considering gene therapy to protect from X‐linked deafness DFNX2 and associated neurodevelopmental disorders

“…To date, over 80 deafness‐causative mutations in the coding sequence of POU3F4 have been identified in some 20 countries, including missense, nonsense, deletion, frameshift, and extension mutations (Figure 1). 6–46 Moreover, deletions of the entire gene as well as deletions, paracentric inversions, and duplications upstream of the gene (containing the putative regulatory elements of POU3F4 transcription) were also reported 12,13,24,47–52 . X‐linked deafness type 2 (DFNX2, locus Xq21.1), caused by POU3F4 mutations, accounts for nearly 50% of all cases of X‐linked hearing loss.…”

“… 5 , 6 To date, over 80 deafness‐causative mutations in the coding sequence of POU3F4 have been identified in some 20 countries, including missense, nonsense, deletion, frameshift, and extension mutations (Figure 1 ). 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 Moreover, deletions of the entire gene as well as deletions, paracentric inversions, and duplications upstream of the gene (containing the putative regulatory elements of POU3F4 transcription) were also reported. 12 , 13 , 24 , 47 , 48 , 49 , 50 ...…”