Nationwide population genetic screening improves outcomes of newborn screening for hearing loss in China

Abstract

The benefits of concurrent newborn hearing and genetic screening have not been statistically proven due to limited sample sizes and outcome data. To fill this gap, we analyzed outcomes of newborns with genetic screening results. Methods: Newborns in China were screened for 20 hearingloss-related genetic variants from 2012 to 2017. Genetic results were categorized as positive, at-risk, inconclusive, or negative. Hearing screening results, risk factors, and up-to-date hearing status were followed up via phone interviews. Results: Following up 12,778 of 1.2 million genetically screened newborns revealed a higher rate of hearing loss by three months of age among referrals from the initial hearing screening (60% vs. 5.0%, P < 0.001) and a lower rate of lost-to-follow-up/documentation (5% vs. 22%, P < 0.001) in the positive group than in the inconclusive group. Importantly, genetic screening detected 13% more hearing-impaired infants than hearing screening alone and identified 2,638 (0.23% of total) newborns predisposed to preventable ototoxicity undetectable by hearing screening. Conclusion: Incorporating genetic screening improves the effectiveness of newborn hearing screening programs by elucidating etiologies, discerning high-risk subgroups for vigilant management, identifying additional children who may benefit from early intervention, and informing at-risk newborns and their maternal relatives of increased susceptibility to ototoxicity.

Phenotypic Heterogeneity of Post-lingual and/or Milder Hearing Loss for the Patients With the GJB2 c.235delC Homozygous Mutation

“…Most patients with the GJB2 c.235delC homozygous mutation show pre-lingual severe to profound hearing impairment (Zhao et al, 2011). However, even cases with the GJB2 c.235delC homozygous mutation may be undetected by newborn hearing screening, suggesting that GJB2 c.235delC homozygous mutation-related hearing loss may not always be congenital at onset (Minami et al, 2013;Dai et al, 2019;Wang et al, 2019). Clinically, except for late-onset hearing impairment, some GJB2 c.235delC homozygous patients show post-lingual and/or mild to moderate hearing impairment instead of profound hearing loss with a highly heterogeneous phenotype.…”

Newborn Screening in Unselected Children Using Genomic Sequencing

“…Previous studies have underlined the importance of newborn screening in early detection and prevention of death or disability. Phenylketonuria (PKU) (28), Congenital Hypothyroidism (CH) (28) and Hearing Loss (29) are included in the national-wide newborn screening program in China, however, many newborn patients and/or carriers remain genetically undiagnosed. This is partly because the gene-bygene or small panel strategies leave little room for the expansion of diseases association.…”

Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach

“…These three genes are known to have hotspot variants causing non-syndromic hearing loss in Asian populations. 27 28 Compared to a single gene test of GJB2 , which is frequently used as the first-tier test to exclude hotspot variants before exome sequencing, 7 11 a multiplex PCR sequencing approach appears to be efficient and cost-effective as it is more flexible to detect hotspot variants across multiple deafness-related genes.…”

“…The results were consistent with the recent findings that newborns with positive genotypes could be missed by physiologic newborn hearing screens but identified by genetic screens, highlighting the necessity of concurrent hearing and genetic screening in newborns. 28 32…”