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. 2018 Dec;20(12):1663-1676.
doi: 10.1038/s41436-018-0004-x. Epub 2018 Jun 15.

Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss

Sarah Sheppard  1   2 , Sawona Biswas  3   4 , Mindy H Li  5 , Vijayakumar Jayaraman  2 , Ian Slack  1 , Edward J Romasko  3   4 , Ariella Sasson  6 , Joshua Brunton  2 , Ramakrishnan Rajagopalan  3   4   6 , Mahdi Sarmady  3   4   6 , Jenica L Abrudan  1   2 , Sowmya Jairam  3   4   7 , Elizabeth T DeChene  4 , Xiahoan Ying  2 , Jiwon Choi  2 , Alisha Wilkens  2   4 , Sarah E Raible  2 , Maria I Scarano  8 , Avni Santani  3   4 , Jeffrey W Pennington  6 , Minjie Luo  3   4 , Laura K Conlin  3   4 , Batsal Devkota  6 , Matthew C Dulik  3   4 , Nancy B Spinner  3   4 , Ian D Krantz  9   10
Affiliations

Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss

Sarah Sheppard et al. Genet Med. 2018 Dec.

Abstract

Purpose: Hearing loss (HL) is the most common sensory disorder in children. Prompt molecular diagnosis may guide screening and management, especially in syndromic cases when HL is the single presenting feature. Exome sequencing (ES) is an appealing diagnostic tool for HL as the genetic causes are highly heterogeneous.

Methods: ES was performed on a prospective cohort of 43 probands with HL. Sequence data were analyzed for primary and secondary findings. Capture and coverage analysis was performed for genes and variants associated with HL.

Results: The diagnostic rate using ES was 37.2%, compared with 15.8% for the clinical HL panel. Secondary findings were discovered in three patients. For 247 genes associated with HL, 94.7% of the exons were targeted for capture and 81.7% of these exons were covered at 20× or greater. Further analysis of 454 randomly selected HL-associated variants showed that 89% were targeted for capture and 75% were covered at a read depth of at least 20×.

Conclusion: ES has an improved yield compared with clinical testing and may capture diagnoses not initially considered due to subtle clinical phenotypes. Technical challenges were identified, including inadequate capture and coverage of HL genes. Additional considerations of ES include secondary findings, cost, and turnaround time.

Keywords: exome sequencing; genetic diagnostics; hearing loss; sensorineural.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1. Capture and coverage analysis for all HL genes, selected variants, and selected HL genes.
a Distribution of exons for HL genes that are targeted for capture by the Agilent SureSelect version 4 capture kit. b Coverage data by exon. c Distribution of selected variants from HL genes that are targeted for capture by the Agilent SureSelect version 4 capture kit. d Coverage data by variant. e Distribution of exons of GJB2, OTOA, and STRC that are targeted for capture by the Agilent SureSelect version 4 capture kit. f Coverage data by exon
See this image and copyright information in PMC

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