Genetic causes of moderate to severe hearing loss point to modifiers

Abstract

The genetic underpinnings of recessively inherited moderate to severe sensorineural hearing loss are not well understood, despite its higher prevalence in comparison to profound deafness. We recruited 92 consanguineous families segregating stable or progressive, recessively inherited moderate or severe hearing loss. We utilized homozygosity mapping, Sanger sequencing, targeted capture of known deafness genes with massively parallel sequencing and whole exome sequencing to identify the molecular basis of hearing loss in these families. Variants of the known deafness genes were found in 69% of the participating families with the SLC26A4, GJB2, MYO15A, TMC1, TMPRSS3, OTOF, MYO7A and CLDN14 genes together accounting for hearing loss in 54% of the families. We identified 20 reported and 21 novel variants in 21 known deafness genes. Sixteen of the twenty reported variants, previously associated with stable, profound deafness were associated with moderate to severe or progressive hearing loss in our families. These data point to a prominent role for genetic background, environmental factors or both as modifiers of human hearing loss severity.

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

“…Seven new likely pathogenic variants (c.945G>A [p.(Trp315*)], c.1143C>G [p.(Tyr381*)], c.1209G>A [p.(Trp403*)], c.1224+2T>C, c.1259G>A [p.(Cys420Tyr)], c.1728C>G [p.(Asn576Lys)], and c.1753_1754insA [p.(Asn407Lysfs*2)]) were identified in our cohort (Table and ). In contrast, the c.482+1986_88delTGA allele of HGF accounts for HL segregating in 26 families (Table ), which was already identified as a founder allele in 50 other Pakistani families in our collaborative studies (Naz et al., ; Rehman et al., ; Schultz et al., ). Similarly, the c.272T>C allele of CIB2 accounts for the HL phenotype segregating in 15 families (Table ).…”

“…For instance, two families (HL007 and DEM4372) display locus heterogeneity, within the same or different branches, segregating homozygous variants in two different known NSARHL genes (Figure ), which further highlights the unexpected complexity of the genetic diagnosis of HL in consanguineous families. In the family HL007, most of the affected individuals are homozygous either for a reported c.1056G>A, p.(Trp352*) variant of TPRN , (Rehman et al., ), or another reported c.7814A>G, p.(Asn2605Ser) variant in CDH23 (Naz et al., ) a gene known to be involved in either NSARHL or Usher syndrome type 1D (MIM# 601067) (Bork et al., ). Affected individual VII:3 is homozygous for both of the likely pathogenic variants of TPRN and CDH23 (Figure ).…”

Single Cell and Single Nucleus RNA-Seq Reveal Cellular Heterogeneity and Homeostatic Regulatory Networks in Adult Mouse Stria Vascularis

“…All scale bars 20 µm. In addition to Slc26a4, deafness genes expressed in spindle cells include Ceacam16, Cldn14, and P2rx2 (Wilcox et al, 2001;Ben-Yosef et al, 2003;Zheng et al, 2011;Faletra et al, 2014;Naz et al, 2017;Zhu et al, 2017;Booth et al, 2018). More importantly, these data demonstrate the possibility that some of these deafness genes affect multiple SV cell types, as in the case of Mitf and Supplementary Figure S9.…”

Molecular epidemiology of Chinese Han deaf patients with bi-allelic and mono-allelic GJB2 mutations

“…Consistent with previous studies [17], all three probands with STRC homozygous or compound heterozygous deletions have moderate hearing loss (PTAs of 40-50 dB HL). Fourteen of the sixteen other independent mutations identified in this study have been reported to be associated with hearing loss in previous studies, including dominant mutations EYA1 c.1276G > A (p. G426S) [18] and MITF c.877C > T (p. R293*) [19], recessive mutations PCDH15 c.4133C > T (p. T1378I) and c.1453delT (p. S485Rfs*2) [20], USH2A c.10904C > A (p.T3635 N) [21], MYO15A c.8158G > A (p. D2720N) and c.10258_10260delTTC (p.F3420-) [22], CDH23 c.7630 T > G (p. L2544 V) and c.8257G > A (p.A2753T) [20], OTOF c.2122C > T (p.R708*) and c.1194 T > A (p.D398E) [23,24], SLC26A4 c.1174A > T (p. N392Y) and c.1975G > C (p.V659 L) [25], and SMPX c.55A > G (p. N19D) [26]. One novel hemizygous mutation, c.201delT (p.E68Sfs*11) in TIMM8A, was identified in a male proband D211 as a likely pathogenic mutation since similar Based on the new genetic diagnosis, we revisited the clinical aspects of proband D289 and D554.…”