Genetic screening for hearing impairment and the genotype-phenotype correlation of GJB2 c.109G>A variants in 47,729 neonates: a population-based study in southern China

This study aimed to characterize the Variant profile of the 4 common deafness-causing genes and evaluated the genotype-phenotype correlation of GJB2 c.109G > A variants in a neonatal cohort, providing insights for early diagnosis of congenital hearing loss.

A total of 47,729 newborns in Shenzhen underwent integrated deafness gene screening (23 common pathogenic variants across GJB2, SLC26A4, MT-RNR1, and GJB3) and two-stage audiometric assessments from January 2022 to November 2024. Participants were stratified into three groups based on GJB2 c.109G > A genotypes: homozygous (Group A, n = 487), compound heterozygous (Group B, n = 87), and heterozygous carriers (Group C, n = 8055). Hearing function was evaluated via otoacoustic emissions (OAE) at 48 h postpartum, with non-passing cases receiving follow-up OAE and auditory brainstem response (ABR) testing at 42 days.

Deafness-associated Variant were detected in 21.56 % (10,291/47,729) of neonates, with GJB2 exhibiting the highest carrier frequency (20.25 %), followed by SLC26A4 (1.44 %), MT-RNR1 (0.28 %), and GJB3 (0.18 %). The GJB2 c.109G > A locus dominated the variant landscape, with a carrier rate of 18.12 % (n = 8649) and an minor allele frequency of 9.57 %. The overall pass rates for the two-stage audiological assessments differed significantly across the groups: 63.66 % (Group A), 70.11 % (Group B), and 98.92 % (Group C). Bilateral hearing impairment predominated in Groups A and B.

The GJB2 c.109G > A Variant represents the most prevalent pathogenic variant in Shenzhen neonates, and the infants carrying deafness-causing genotypes of this variant presents relatively high hearing screening pass rate. Integrated genetic and audiometric screening could enhance early identification of high-risk infants.