Author + information
- Received December 20, 2017
- Revision received March 18, 2018
- Accepted April 24, 2018
- Published online July 16, 2018.
- Richard D. Bagnall, PhDa,b,
- Jodie Ingles, MPH, PhDa,b,c,
- Marcel E. Dinger, PhDd,e,
- Mark J. Cowley, PhDd,e,
- Samantha Barratt Ross, BMedScia,b,
- André E. Minoche, PhDd,
- Sean Lal, MBBS, PhDb,c,
- Christian Turner, MBBSf,
- Alison Colley, MBBS, MMedScg,
- Sulekha Rajagopalan, MBBSg,
- Yemima Berman, MBBS, PhDh,
- Anne Ronan, MRCP, MEpidi,j,
- Diane Fatkin, MBBSe,k,l and
- Christopher Semsarian, MBBS, PhD, MPHa,b,c,∗ (, )@CSHeartResearch
- aAgnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia
- bSydney Medical School, University of Sydney, Sydney, New South Wales, Australia
- cDepartment of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- dGarvan Institute of Medical Research, Sydney, New South Wales, Australia
- eSt. Vincent’s Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia
- fThe Sydney Children’s Hospital, Westmead, New South Wales, Australia
- gDepartment of Clinical Genetics, Liverpool Hospital, Liverpool, New South Wales, Australia
- hClinical Genetics Department, Royal North Shore Hospital, Sydney, New South Wales, Australia
- iHunter Genetics Unit, Newcastle, New South Wales, Australia
- jUniversity of Newcastle, Newcastle, New South Wales, Australia
- kMolecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
- lCardiology Department, St. Vincent’s Hospital, Sydney, New South Wales, Australia
- ↵∗Address for correspondence:
Dr. Christopher Semsarian, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Missenden Road, Newtown, NSW 2042, Australia.
Background Whole genome sequencing (WGS) is a comprehensive genetic testing approach that reports most types of nucleotide variants.
Objectives This study sought to assess WGS for hypertrophic cardiomyopathy (HCM) in which prior genetic testing did not establish a molecular diagnosis, and as a first-line genetic test.
Methods WGS was performed on 58 unrelated patients with HCM, 14 affected family members, and 2 unaffected parents of a severely affected proband. The authors searched for nucleotide variants in coding regions of 184 candidate cardiac hypertrophy genes. They also searched for nucleotide variants in deep intronic regions that alter RNA splicing, large genomic rearrangements, and mitochondrial genome variants. RNA analysis was performed to validate splice-altering variants.
Results The authors found a pathogenic or likely pathogenic variant in 9 of 46 families (20%) for which prior genetic testing was inconclusive. Three families had variants in genes not included in prior genetic testing. One family had a pathogenic variant that was filtered out with prior exome sequencing. Five families had pathogenic variants in noncoding regions, including 4 with deep intronic variants that activate novel splicing, and 1 mitochondrial genome variant. As a first-line genetic test, WGS identified a pathogenic variant in 5 of 12 families (42%) that had never received prior genetic testing.
Conclusions WGS identified additional genetic causes of HCM over targeted gene sequencing approaches. Extending genetic screening to deep intronic regions identified pathogenic variants in 9% of gene-elusive HCM. These findings translate to more accurate diagnosis and management in HCM families.
This research is supported by a grant from NSW Health Genomics Collaborative Grants Program. Dr. Ingles is a recipient of a Heart Foundation of Australia Future Leader Fellowship (#100833). Dr. Semsarian is the recipient of a National Health and Medical Research Council (NHMRC) Practitioner Fellowship (#1059156). Dr. Dinger is an employee of Genome.One, a commercial genetic testing company. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received December 20, 2017.
- Revision received March 18, 2018.
- Accepted April 24, 2018.
- 2018 American College of Cardiology Foundation
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