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Reprinted by permission of Hum Genet. 2016; 135(4):441-450.

Hum Genet (2016) 135:441–450 DOI 10.1007/s00439-016-1648-8

ORIGINAL INVESTIGATION

Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss

Christina M. Sloan‑Heggen 1,2  · Amanda O. Bierer 1  · A. Eliot Shearer 1  · Diana L. Kolbe 1  · Carla J. Nishimura 1  · Kathy L. Frees 1  · Sean S. Ephraim 1  · Seiji B. Shibata 1  · Kevin T. Booth 1  · Colleen A. Campbell 1  · Paul T. Ranum 1  · Amy E. Weaver 1  · E. Ann Black‑Ziegelbein 1  · Donghong Wang 1  · Hela Azaiez 1  · Richard J. H. Smith 1,2,3

Received: 16 December 2015 / Accepted: 14 February 2016 / Published online: 11 March 2016 © The Author(s) 2016. This article is published with open access at Springerlink.com

Abstract  Hearing loss is the most common sensory deficit in humans, affecting 1 in 500 newborns. Due to its genetic heterogeneity, comprehensive diagnostic testing has not previously been completed in a large multiethnic cohort. To determine the aggregate contribution inheritance makes to non-syndromic hearing loss, we performed com- prehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients. No patient was excluded based on phenotype, inheritance or previous testing. Test- ing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39 %). Patho- genic variants were found in 49 genes and included mis- sense variants (49 %), large copy number changes (18 %), small insertions and deletions (18 %), nonsense variants (8 %), splice-site alterations (6 %), and promoter variants (<1 %). The diagnostic rate varied considerably based on

phenotype and was highest for patients with a positive fam- ily history of hearing loss or when the loss was congenital and symmetric. The spectrum of implicated genes showed wide ethnic variability. These findings support the more efficient utilization of medical resources through the devel- opment of evidence-based algorithms for the diagnosis of hearing loss.

Introduction

Hearing loss is the most common sensory deficit in humans. It is diagnosed in 1 in 500 newborns and affects half of all octogenarians (Fortnum et al. 2001 ; Morton and Nance 2006 ). Although causality is multifactorial, in devel- oped countries, a large fraction of hearing loss is genetic and non-syndromic, i.e., not associated with other pheno- types (Marazita et al. 1993 ). Non-syndromic hearing loss (NSHL) mimics are syndromic forms of hearing loss that present as NSHL early in life with syndromic features developing later. Type 1 Usher syndrome, for example, is an NSHL mimic presenting as congenital profound hearing loss with delayed motor milestones. The associated pro- gressive vision loss begins in late childhood (Smith et al. 1994 ). Genetic diagnosis of NSHL and NSHL mimics is valua- ble. It provides prognostic information on possible progres- sion of hearing loss, permits meaningful genetic counseling, and impacts treatment decisions (Kimberling et al. 2010 ). A positive diagnosis also saves healthcare dollars by direct- ing the clinical evaluation and obviating unnecessary testing such as the routine use of imaging. The challenge, however, is in providing comprehensive genetic testing. Hearing loss is extremely heterogeneous, with over 90 genes causally implicated in NSHL (Van Camp and Smith 2015 ). Although

A. O. Bierer, A. E. Shearer, and D. L. Kolbe all contributed equally to this work.

Electronic supplementary material  The online version of this article (doi: 10.1007/s00439-016-1648-8 ) contains supplementary material, which is available to authorized users.

Richard J. H. Smith richard‑smith@uiowa.edu

*

1 Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology—Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA 2 Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City  52242, IA, USA 3 Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City 52242, IA, USA

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