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Genet Med. 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.

Author information

1
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
3
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4
Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
5
Division of Genetics, Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA.
6
Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
7
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8
Division of Genetics, Cooper University Health Care, Camden, NY, USA.
9
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. krantz@email.chop.edu.
10
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. krantz@email.chop.edu.

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

PMID:
29907799
PMCID:
PMC6295269
DOI:
10.1038/s41436-018-0004-x
[Indexed for MEDLINE]
Free PMC Article

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