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Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy.
- Source :
-
Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2018 Nov; Vol. 20 (11), pp. 1374-1386. Date of Electronic Publication: 2018 Mar 08. - Publication Year :
- 2018
-
Abstract
- Purpose: We evaluated the diagnostic yield in pediatric dilated cardiomyopathy (DCM) of combining exome sequencing (ES)-based targeted analysis and genome-wide copy-number variation (CNV) analysis. Based on our findings, we retrospectively designed an effective approach for genetic testing in pediatric DCM.<br />Methods: We identified 95 patients (in 85 families) with pediatric onset of DCM. We initially excluded 13 of these families because they already had a genetic diagnosis, leaving a total of 31 probands for single-nucleotide polymorphism (SNP) array and trio-ES. We used Human Phenotype Ontology (HPO)-based filtering for our data analysis.<br />Results: We reached a genetic diagnosis in 15/31 (48.4%) families. ES yielded a diagnosis in 13 probands (13/15; 86.7%), with most variants being found in genes encoding structural cardiomyocyte components. Two large deletions were identified using SNP array. If we had included the 13 excluded families, our estimated yield would have been 54%.<br />Conclusion: We propose a standardized, stepwise analysis of (i) well-known cardiomyopathy genes, (ii) CNVs, (iii) all genes assigned to HPO cardiomyopathy, and (iv) if appropriate, genes assigned to other HPO terms. This diagnostic approach yields the highest increase at each subsequent step and reduces analytic effort, cost, the number of variants of unknown clinical significance, and the chance of incidental findings.
- Subjects :
- Adolescent
Cardiomyopathy, Dilated pathology
Child
Child, Preschool
Exome genetics
Female
Humans
Male
Pedigree
Polymorphism, Single Nucleotide genetics
Sequence Analysis, DNA
Sequence Deletion genetics
Exome Sequencing
Cardiomyopathy, Dilated diagnosis
Cardiomyopathy, Dilated genetics
DNA Copy Number Variations genetics
Genetic Testing methods
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0366
- Volume :
- 20
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Genetics in medicine : official journal of the American College of Medical Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 29517769
- Full Text :
- https://doi.org/10.1038/gim.2018.9