Dataset Information

Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss.

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.

SUBMITTER: Sheppard S

PROVIDER: S-EPMC6295269 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss.

Sheppard Sarah S Biswas Sawona S Li Mindy H MH Jayaraman Vijayakumar V Slack Ian I Romasko Edward J EJ Sasson Ariella A Brunton Joshua J Rajagopalan Ramakrishnan R Sarmady Mahdi M Abrudan Jenica L JL Jairam Sowmya S DeChene Elizabeth T ET Ying Xiahoan X Choi Jiwon J Wilkens Alisha A Raible Sarah E SE Scarano Maria I MI Santani Avni A Pennington Jeffrey W JW Luo Minjie M Conlin Laura K LK Devkota Batsal B Dulik Matthew C MC Spinner Nancy B NB Krantz Ian D ID

Genetics in medicine : official journal of the American College of Medical Genetics 20180615 12

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 29907799

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Project description:BackgroundConditions associated with sudden cardiac arrest/death (SCA/D) in youth often have a genetic etiology. While SCA/D is uncommon, a pro-active family screening approach may identify these inherited structural and electrical abnormalities prior to symptomatic events and allow appropriate surveillance and treatment. This study investigated the diagnostic utility of exome sequencing (ES) by evaluating the capture and coverage of genes related to SCA/D.MethodsSamples from 102 individuals (13 with known molecular etiologies for SCA/D, 30 individuals without known molecular etiologies for SCA/D and 59 with other conditions) were analyzed following exome capture and sequencing at an average read depth of 100X. Reads were mapped to human genome GRCh37 using Novoalign, and post-processing and analysis was done using Picard and GATK. A total of 103 genes (2,190 exons) related to SCA/D were used as a primary filter. An additional 100 random variants within the targeted genes associated with SCA/D were also selected and evaluated for depth of sequencing and coverage. Although the primary objective was to evaluate the adequacy of depth of sequencing and coverage of targeted SCA/D genes and not for primary diagnosis, all patients who had SCA/D (known or unknown molecular etiologies) were evaluated with the project's variant analysis pipeline to determine if the molecular etiologies could be successfully identified.ResultsThe majority of exons (97.6 %) were captured and fully covered on average at minimum of 20x sequencing depth. The proportion of unique genomic positions reported within poorly covered exons remained small (4 %). Exonic regions with less coverage reflect the need to enrich these areas to improve coverage. Despite limitations in coverage, we identified 100 % of cases with a prior known molecular etiology for SCA/D, and analysis of an additional 30 individuals with SCA/D but no known molecular etiology revealed a diagnostic answer in 5/30 (17 %). We also demonstrated 95 % of 100 randomly selected reported variants within our targeted genes would have been picked up on ES based on our coverage analysis.ConclusionsES is a helpful clinical diagnostic tool for SCA/D given its potential to successfully identify a molecular diagnosis, but clinicians should be aware of limitations of available platforms from technical and diagnostic perspectives.

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Dataset Information

Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss.

Purpose

Methods

Results

Conclusion

Publications

Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss.

Similar Datasets

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