Comprehensive genotype-phenotype correlation analysis in 11 509 neonates carrying common deafness-associated pathogenic variants.

Large-scale genotype-phenotype correlations in 11,509 neonates with pathogenic variants in common deafness genes; comparison of GJB2 c.235del vs c.109G>A profiles

In a cohort of 11,509 neonates carrying at least one pathogenic variant in GJB2, SLC26A4, MT-RNR1, or GJB3, only 58 had confirmed hearing loss — of whom 15.52% had passed the initial audiological screening. GJB2 c.235del homozygotes showed markedly higher (50%) and more severe hearing loss than GJB2 c.109G>A homozygotes (6.51%). Sanger sequencing reclassified 23% of presumed heterozygotes as compound heterozygotes. This work highlights the gap between genetic and neonatal audiological screening, and the need for prolonged audiological follow-up.

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This study shows that classical neonatal hearing screening misses a non-negligible fraction of genetically at-risk children — a strong argument for complementary genomic newborn screening. The phenotypic distinction between c.235del and c.109G>A is directly actionable to stratify the intensity of audiological follow-up from birth.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 1/2 · Sample size: 1/1 · Journal quality: 1/1 → Total: 7/10