Concurrent physiologic and gene-based genetic newborn hearing screening in a general population

Physiologic newborn hearing screening (NBHS) has several weaknesses requiring improvement. Studies have explored variant-based genetic NBHS as a complement to physiologic NBHS. However, this genetic NBHS strategy has fundamental limitations that challenge logistics. Given findings that a small set of genes accounts for the majority of genetic etiologies of hearing loss (HL), we designed a gene-based genetic NBHS strategy that screens for genes instead of limited variants, targeting the coding regions of twelve HL-related genes and the aminoglycoside-induced HL risk gene MT-RNR1. Our cohort study was conducted at Nanjing Women and Children’s Healthcare Hospital in China, between March 2022 and July 2023. All participants were offered concurrent physiologic and gene-based genetic NBHS. Infants with positive physiologic or genetic NBHS results were scheduled for audiological assessments. Of 20,997 participants with eligible physiologic and genetic NBHS results, 164 (0.8%) had positive physiologic or genetic NBHS results. Of 150 who underwent audiological assessments, 77 had confirmed HL. Among them, 32 were identified by genetic NBHS only, 24 by both physiologic and genetic NBHS, and 21 by physiologic NBHS only. Compared with conventional physiologic NBHS protocol (identified 45 HL cases), incorporating gene-based genetic NBHS into physiologic NBHS (additionally identified 32 HL cases) only required an additional 0.4% (87/20,997) of infants to undergo audiological assessments, yet achieved a 71% (32/45) increase in HL identification and provided genetic etiological information for 73% (56/77) of all HL cases. For 21 HL cases identified by physiologic NBHS only, genome sequencing identified genetic findings in three additional cases, showing that up to 77% (59/77) of infants with HL were caused by genetic factors in this general newborn population. Our new comprehensive NBHS protocol, concurrent physiologic and gene-based genetic NBHS, significantly improved the identification of infants with HL. The results demonstrated that the gene-based genetic NBHS addressed fundamental limitations of the variant-based strategy and was a powerful complement to physiologic NBHS.