Exome sequencing in infants with congenital hearing impairment: a population-based cohort study

Abstract

Congenital hearing impairment (HI) is the most common sensory impairment and can be isolated or part of a syndrome. Diagnosis through newborn hearing screening and management through early intervention, hearing aids and cochlear implantation is well established in the Australian setting; however understanding the genetic basis of congenital HI has been missing. This population-derived cohort comprised infants with moderate-profound bilateral HI born in the 2016-2017 calendar years, detected through newborn hearing screening. Participants were recruited through an integrated paediatric, otolaryngology and genetics HI clinic and offered whole exome sequencing (WES) on a HiSeq4000 or NextSeq500 (Illumina) platform with a targeted average sequencing depth of 100x and chromosome microarray on the Illumina Infinium core exome-24v1.2 platform. Of those approached, 68% (106/156) consented to participate. The rate of genetic diagnosis was 56% (59/106), significantly higher than standard of care (GJB2/6 sequencing only), 21% (22/106). There were clinical implications for the 106 participants: 36% required no further screening, 9% had tailored screening initiated, 2% were offered treatment and 4% had informed care for a complex neurodevelopmental syndrome. WES in this cohort demonstrates the range of diagnoses associated with congenital HI and confirms the genetic heterogeneity of congenital HI. The high diagnostic yield and clinical implications emphasises the need for genomic sequencing to become standard of care.

Exome Sequencing for Isolated Congenital Hearing Loss: A Cost‐Effectiveness Analysis

“…The study utilized data from a population-derived cohort of infants who received ES early in the trajectory of care (prior to 1 year of age), as part of the Melbourne Genomics Health Alliance Congenital Deafness flagship, 9 and other published secondary evidence. For the primary clinical study, published in detail, [8][9][10] and briefly described here, 106 infants were recruited and offered ES with targeted analysis of deafness genes (available from https://panelapp.agha.umccr.org/panels/209/ and listed in Table I) and multiplex ligation-dependent probe amplification (MLPA) for OTOA/STRC. This cohort included infants with bilateral congenital sensorineural HL with ≥40 dB of loss in the best ear, including syndromic and non-syndromic presentations ascertained over a two-year period.…”

“…1) was designed to model the diagnostic pathway with and without ES for this cohort. The decision tree is based on results of the primary study 8 and recommended investigations for children with congenital HL. 11 The primary study findings were that 22/106 participants had GJB2/6 pathogenic variants, 16/106 had another non syndromic genetic cause, and 21/106 had a syndrome diagnosis.…”

“…For those with a syndromic diagnosis, tailored care was provided. We have previously recommended that sequencing of GJB2/6 be offered prior to ES, 6 and have designed our model based on this approach. Standard care is that all children diagnosed with congenital HL are offered an appointment with a pediatrician and investigation with GJB2/6 sequencing.…”

“…5 The majority of congenital hearing loss (HL) has a genetic etiology. 6 Despite a recommendation that ES becomes standard of care for this indication, 7 this has largely not been implemented. This is due to resource limitations and the scarcity of data demonstrating costeffectiveness and clinical utility.…”

“…In a recent study investigating the genetic causes of congenital HL, we identified a high clinical utility in the diagnosed cohort. 8 Care was able to be streamlined and many diagnostic investigations avoided. In this follow-up analysis, we examine the cost-effectiveness of ES for children presenting with isolated HL relative to standard care.…”