Genetic studies identify known and novel variants for recessively inherited moderate to severe hearing loss in consanguineous families from Pakistan.

Variants of at least twenty-seven human genes are associated with stable or progressive nonsyndromic moderate to severe hearing loss inherited as a recessive condition. We ascertained 54 consanguineous families, predominantly from the Punjab province in Pakistan, with multiple individuals affected by moderate to severe or progressively profound hearing loss. After Sanger sequencing identified 4 families with GJB2 variants or a non-coding pathogenic variant in HGF, exome sequencing was carried out for selected samples from the remaining 50 families. Analyses revealed a total of 24 novel and 33 reported variants in 26 different genes associated with hearing loss. Overall, there were 23 missense variants, 3 in-frame deletions and 1 intronic deletion, while 30 variants likely impacted splicing, introduced premature termination codons or caused frameshifts. Thus, over half of the alleles are predicted to severely impair gene function. Genetic heterogeneity was observed in members of 9 families. Variants of SLC26A4 were key contributors with a frequency of 30%, while those affecting CDH23, MYO15A, GJB2 and OTOF explained 28% of hearing loss. Our findings corroborate the contribution of many well-studied gene variants associated with hearing loss and also implicate LHFPL5 and PCDH15 in the etiology of moderate or progressive hearing loss.