Identification of MYO7A Variants in Consanguineous Pakistani Families with Syndromic Hearing Loss

Background: Hearing loss (HL) is a genetically and clinically heterogeneous sensorineural disorder. The World Health Organization estimates that ∼1.5 billion people worldwide currently live with some degree of HL (all causes and severities combined), a burden projected to rise to 2.5 billion by 2050. A substantial proportion of early-onset and congenital HL is attributable to genetic causes, particularly in populations with a high rate of consanguinity, such as Pakistan, where consanguinity increases the prevalence of autosomal recessive disorders and thereby enriches the genetic landscape of hereditary HL. Methods: In this study, two consanguineous families (HL-76 and HL-79) presenting with HL and vision impairment as phenotypes were ascertained from the province of Balochistan, Pakistan. Results: Exome sequencing (ES) followed by Sanger sequencing revealed cosegregation of MYO7A variants c.487G > A p.(Gly163Arg) and c.4079A > G p.(Asp1360Gly) in families HL-79 and HL-76, respectively. Bi-allelic variants in MYO7A are known to cause Usher syndrome type 1, characterized by deafness, progressive vision loss, and vestibular areflexia. The variants identified in our cohort were predicted to be damaging by in silico analysis. Conclusion: The p.(Asp1360Gly) variant identified in family HL-76 represents a potentially novel contribution to the MYO7A mutational spectrum, whereas p.(Gly163Arg) identified in family HL-79 is a recurrent variant previously classified as pathogenic/likely pathogenic in ClinVar and in prior published reports. Together, these findings establish a molecular diagnosis for both families, with direct implications for genetic counseling and clinical management.