Large scale newborn deafness genetic screening of 142,417 neonates in Wuhan, China

Abstract

Almost one third of the three million people in China suffering severe deafness are children, and 50% of these cases are believed to have genetic components to their etiology. Newborn hearing genetic screening can complement Universal Neonatal Hearing Screening for the diagnosis of congenital hearing loss as well as identifying children at risk for late-onset and progressive hearing impairment. The aim of this joint academic and Ministry of Health project was to prototype a cost effective newborn genetic screen in a community health setting on a city-wide level, and to ascertain the prevalence of variation at loci that have been associated with non-syndromic hearing loss. With the participation of 143 local hospitals in the city of Wuhan, China we screened 142,417 neonates born between May 2014 and Dec. 2015. The variants GJB2 c.235delC, SLC26A4 c.919-2A>G, and mitochondrial variants m.1555A>G and m.1494C>T were assayed using real time PCR. Newborns found to carry a variant were re-assayed by sequencing in duplicate. Within a subset of 707 newborns we assayed using real-time PCR and ARMS-PCR to compare cost, sensitivity and operating procedure. The most frequent hearing loss associated allele detected in this population was the 235delC variant in GJB2 gene. In total, 4289 (3.01%) newborns were found to carry at least one allele of either GJB2 c.235delC, SLC26A4 c.919-2A>G or two assayed MT-RNR1 variants. There was complete accordance between the real-time PCR and the ARMS PCR, though the real-time PCR had a much lower failure rate. Real-time PCR had a lower cost and operating time than ARMS PCR. Ongoing collaboration with the participating hospitals will determine the specificity and sensitivity of the association of the variants with hearing loss at birth and arising in early childhood, allowing an estimation of the benefits of newborn hearing genetic screening in a large-scale community setting.

A proposal for comprehensive newborn hearing screening to improve identification of deaf and hard-of-hearing children

“…51–53 The largest study to date of 142,417 Chinese newborns identified a carrier rate of 3.01% for the four most common genetic causes of deafness but did not include audiologic data to determine how genetic screening could augment physiologic screening. 54 This variability in detection rates might reflect differences in sample sizes, variants screened, and screening methodologies; however, the data do indicate that even limited genetic screening can identify newborns who otherwise would have been missed by physiologic screening alone.…”

Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn screening

“…Two genes MMACHC and MUT were screened and identified 11 patients with MMACHC and three with MUT gene mutations, thus estimated total incidence of 1:16,883. 20 Similarly, a large scale newborn screening of 142,417 neonates for common genetic deafness disorder revealed total 4289 (3.01%) newborns carrying at least one allele of the disease-causing gene GJB2 c.235delC, SLC26A4 c.919-2A>G and mitochondrial variants m.1555A>G and m.1494C>T. 21 Estimating the carrier frequency from Saudi population, Abouelhoda et al, 21 observed highest carrier frequency of 0.0218 for CYP1B1 gene mutation (c.1103G>A: p.Arg368His), which causes congenital glaucoma and considered as a founder mutation. Similarly, carrier frequency for variant (c.20A>T: p.Glu7Val) in the HBB gene was observed as 0.0228, which causes thalassemia and sickle cell anemia.…”

Panel-based NGS reveals disease-causing mutations in hearing loss patients using BGISEQ-500 platform

“…In the past few years, large scale genetic screenings of HL have been performed, [12,13] however, most of these studies only focused on several most common variants (such as c.235delC of GJB2 , c.919-2A>G of SLC26A4 , and mitochondrial m.1555A>G). Accurate and timely detection of other disease-causing mutations and related genes play a pivotal role in patients with HL.…”

“…[12] Hao et al screened 142,417 neonates from Wuhan using 4 recurrent deafness mutations, including 1 mutation in gene GJB2 (c.235delC), 1 mutation in gene SLC26A4 (c.919-2A>G), and 2 mitochondrial mutations (m.1494C>T and m.1555A>G). [13] However, genetic hearing screening using a small number of recurrent mutations is insufficient. To date, there are more than a 100 genes described to be related to HL.…”