Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families

Abstract

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

Keywords: Pakistan; consanguinity; exome sequencing; genetic diagnosis; genome-wide linkage analysis; hearing loss.

Figure 1

Pedigree and segregation analysis of known and previously undescribed variants in 13 Pakistani families with HL. All the families have a consanguineous background, marked with double lines. Affected individuals are shown in black symbols, and unaffected parents and siblings are shown in unfilled symbols. Individuals with a bone disorder, but without HL, are shown in striped symbols. Probands who were exome sequenced are marked with an arrow. Deceased individuals are marked with a diagonal line. The mutated and wild type alleles are illustrated with “−” (mutated) and “+” (wild type) symbols, respectively.

Figure 2

Clinical aspects of patients with previously unreported variants. (A) Affected individuals in family 1 (IV.1, IV.2, IV.3) and family 2 (only III.5, III.10, IV.2, IV.5 were available for photographs) show cupped ears and report severe HL. (B) Pure-tone audiogram for affected family members IV.1 (blue) and IV.2 (red) in family 7. Left-ear measurements are represented as “x” and right-ear measurements are shown with “o”.

Figure 3

Overview of the affected genes and the distribution of different variant types in Pakistani families with HL. (A) Overall percentage of each affected gene in 13 Pakistani families. (B) Number of identified variants by type (missense, nonsense, frameshift, splice-site). The color code refers to the genes that are marked in (A).