Advancing genetic testing for deafness with genomic technology

A Eliot Shearer; E Ann Black-Ziegelbein; Michael S Hildebrand; Robert W Eppsteiner; Harini Ravi; Swati Joshi; Angelica C Guiffre; Christina M Sloan; Scott Happe; Susanna D Howard; Barbara Novak; Adam P Deluca; Kyle R Taylor; Todd E Scheetz; Terry A Braun; Thomas L Casavant; William J Kimberling; Emily M Leproust; Richard J H Smith

doi:10.1136/jmedgenet-2013-101749

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Advancing genetic testing for deafness with genomic technology

Journal article

Open access

Peer reviewed

Advancing genetic testing for deafness with genomic technology

A Eliot Shearer, E Ann Black-Ziegelbein, Michael S Hildebrand, Robert W Eppsteiner, Harini Ravi, Swati Joshi, Angelica C Guiffre, Christina M Sloan, Scott Happe, Susanna D Howard, …

Journal of medical genetics, Vol.50(9), pp.627-634

09/2013

DOI: 10.1136/jmedgenet-2013-101749

PMCID: PMC3887546

PMID: 23804846

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https://www.ncbi.nlm.nih.gov/pmc/articles/3887546View

Open Access

Abstract

Non-syndromic hearing loss (NSHL) is the most common sensory impairment in humans. Until recently its extreme genetic heterogeneity precluded comprehensive genetic testing. Using a platform that couples targeted genomic enrichment (TGE) and massively parallel sequencing (MPS) to sequence all exons of all genes implicated in NSHL, we tested 100 persons with presumed genetic NSHL and in so doing established sequencing requirements for maximum sensitivity and defined MPS quality score metrics that obviate Sanger validation of variants. We examined DNA from 100 sequentially collected probands with presumed genetic NSHL without exclusions due to inheritance, previous genetic testing, or type of hearing loss. We performed TGE using post-capture multiplexing in variable pool sizes followed by Illumina sequencing. We developed a local Galaxy installation on a high performance computing cluster for bioinformatics analysis. To obtain maximum variant sensitivity with this platform 3.2-6.3 million total mapped sequencing reads per sample were required. Quality score analysis showed that Sanger validation was not required for 95% of variants. Our overall diagnostic rate was 42%, but this varied by clinical features from 0% for persons with asymmetric hearing loss to 56% for persons with bilateral autosomal recessive NSHL. These findings will direct the use of TGE and MPS strategies for genetic diagnosis for NSHL. Our diagnostic rate highlights the need for further research on genetic deafness focused on novel gene identification and an improved understanding of the role of non-exonic mutations. The unsolved families we have identified provide a valuable resource to address these areas.

Reproducibility of Results

Deafness - genetics

Humans

Adolescent

Adult

Female

Male

Polymorphism, Single Nucleotide

Genomics - methods

Genetic Testing - methods

Sequence Analysis, DNA

Details

Title: Subtitle: Advancing genetic testing for deafness with genomic technology
Creators: A Eliot Shearer - Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
E Ann Black-Ziegelbein
Michael S Hildebrand
Robert W Eppsteiner
Harini Ravi
Swati Joshi
Angelica C Guiffre
Christina M Sloan
Scott Happe
Susanna D Howard
Barbara Novak
Adam P Deluca
Kyle R Taylor
Todd E Scheetz
Terry A Braun
Thomas L Casavant
William J Kimberling
Emily M Leproust
Richard J H Smith
Resource Type: Journal article
Publication Details: Journal of medical genetics, Vol.50(9), pp.627-634
DOI: 10.1136/jmedgenet-2013-101749
PMID: 23804846
PMCID: PMC3887546
NLM abbreviation: J Med Genet
ISSN: 1468-6244
eISSN: 1468-6244
Publisher: England
Grant note: DC002842 / NIDCD NIH HHS 1F30DC011674 / NIDCD NIH HHS R01 DC003544 / NIDCD NIH HHS R01 DC012049 / NIDCD NIH HHS DC012049 / NIDCD NIH HHS F30 DC011674 / NIDCD NIH HHS R01 DC002842 / NIDCD NIH HHS DC003544 / NIDCD NIH HHS
Language: English
Date published: 09/2013
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Center for Bioinformatics and Computational Biology; Otolaryngology; Internal Medicine; Ophthalmology and Visual Sciences
Record Identifier: 9983979964402771

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