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Hum Genet (2016) 135:441–450
DOI 10.1007/
s00439-016-1648-8ORIGINAL 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.comphenotype 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
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
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.edu1
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
Reprinted by permission of Hum Genet. 2016; 135(4):441-450.
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