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. 2016 Apr;135(4):441-450.
doi: 10.1007/s00439-016-1648-8. Epub 2016 Mar 11.

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  3   4   5
Affiliations

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

Christina M Sloan-Heggen et al. Hum Genet. 2016 Apr.

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 comprehensive 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. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39%). Pathogenic variants were found in 49 genes and included missense 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 family 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 development of evidence-based algorithms for the diagnosis of hearing loss.

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Figures

Fig. 1
Fig. 1
Diagnostic rates are dependent on patient-specific clinical and phenotypic characteristics and are shown as the percentage of patients with the noted characteristic. Background shading separates categories. N for each characteristic is listed after the label. Dashed line indicates the overall diagnostic rate for this study (39.3 %). Fisher exact test used to determine statistical significance with *p < 0.05 and **p < 0.005
Fig. 2
Fig. 2
Diagnostic rate is influenced by ethnic, clinical and phenotypic characteristics. a N for each combination of two reported characteristics for all combinations. Color/shading reflects the number of patients with the paired criteria, up to the maximum of n = 683. b Diagnostic success for each corresponding category in a. Coloring/shading indicative of diagnosis: light orange indicates below average diagnostic rate, yellow indicates close to average diagnostic rate (39.3 %), and dark green indicates above average diagnostic rate. Empty squares had fewer than 10 individuals. AD autosomal dominant, AR autosomal recessive, PE physical exam, DFNB1 prior genetic DFNB1 (GJB2) testing, DFNB1 & other prior genetic testing including DFNB1 and other tests, other testing prior genetic testing excluding DFNB1 testing
Fig. 3
Fig. 3
Solve rate and implicated genes across ethnicities. The 10 genes with ≥10 diagnosis for the entire cohort are plotted individually; all other genes diagnosed are grouped as “other”. Ethnic-specific differences are readily apparent
Fig. 4
Fig. 4
Recommended diagnostic workflow of a patient with hearing loss showing the value of comprehensive genetic testing (CGT) with TGE and the expected diagnostic rate in percentage. A thorough physical and history is essential and determine the expected outcome of CGT. Patients with complex phenotypes may require referral to specialists. Additional phenotypic information on select syndromes is presented in Table S6. Questions regarding the appropriateness of testing can be sent to morl@uiowa.edu. PE physical exam, CGT comprehensive genetic testing, NSHL non-syndromic hearing loss, TFT thyroid function test. aSeveral forms of syndromic hearing loss may present as NSHL and are referred to as ‘NSHL mimics’. CGT includes the diagnosis of these NSHL mimics. bCommon syndromes that can be detected by an otolaryngologist and are targeted by this CGT include Usher syndrome, Pendred syndrome and BOR syndrome. For a complete list of syndromes included on the current CGT panel see Table S8. cSome individuals will present with extremely rare/private syndromes or phenotypes that reflect the co-occurrence of two (or rarely more) syndromes. CGT should be considered for the latter cohort of patients. CGT with the OtoSCOPE panel is not indicated in patients with neurological findings such as epilepsy, intellectual delay and autism, and in patients with complex multisystem syndromes that include hearing loss caused by genes NOT targeted for capture by OtoSCOPE
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