Screening for hearing impairment in newborns using targeted genomic sequencing: a large pilot cohort study.

Objective: Current state-run newborn hearing screening (NBHS) programs have limitations in identifying children with mild or late-onset sensorineural hearing impairment (SNHI). As more than 50% of pediatric SNHI cases are attributed to genetic causes, these limitations may be addressed by the increasing accessibility of high-throughput, low-cost genomic sequencing. This study aims to investigate the feasibility of integrating a next-generation sequencing (NGS)-based genomic screening protocol into conventional NBHS and to examine its potential benefits and challenges.

Methods: A total of 8,261 newborns who underwent simultaneous NBHS and NGSbased genomic screening targeting 46 deafness genes were prospectively enrolled in this study. The genotypes of the subjects were determined, and newborns with conclusive genetic diagnoses were subjected to audiological assessments.

Results: A total of 164 subjects were confirmed to have conclusive genetic diagnoses, with 112 subjects carrying variants in GJB2 and MTRNR1, and 52 subjects carrying variants in other deafness genes. Of these, 126 subjects with conclusive genetic diagnoses passed the NBHS, suggesting that an additional 1.5% (126/8,261) of children at risk for SNHI but not detected by conventional physiological NBHS could be identified through targeted genomic screening in the general population. Notably, the father of one subject with the COL4A5 variant and three paternal relatives of another subject with the EDNRB variant, who were unaware of their conditions prior to this study, were diagnosed with Alport and Waardenburg syndromes, respectively, highlighting the benefit to families.

Conclusion: Targeted genomic sequencing in newborns may complement the conventional NBHS in identifying children at risk for SNHI and facilitate early diagnosis in families with non-syndromic mimics.