Causative Variants for Inherited Cardiac Conditions in a Southeast Asian Population Cohort

Author:

Tomar Swati12ORCID,Klinzing David C.1234,Chen Ching Kit12ORCID,Gan Louis Hanqiang12ORCID,Moscarello Tia5ORCID,Reuter Chloe5ORCID,Ashley Euan A.5ORCID,Foo Roger126ORCID

Affiliation:

1. Cardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University Singapore (S.T., D.C.K., C.K.C., L.H.G., R.F.).

2. Cardiovascular Research Institute, National University Heart Centre (S.T., D.C.K., C.K.C., L.H.G., R.F.), National University Health System, Singapore.

3. Khoo Teck Puat National University Children’s Medical Institute (C.K.C.), National University Health System, Singapore.

4. Department of Pediatrics, Yong Loo Lin School of Medicine, National University Singapore, Singapore (C.K.C.).

5. Centre for Inherited Cardiovascular Disease, Stanford University Medical Center, CA (T.M., C.R., E.A.A.).

6. Genome Institute of Singapore (R.F.).

Abstract

Background: Variable penetrance and late-onset phenotypes are key challenges for classifying causal as well as incidental findings in inherited cardiac conditions. Allele frequencies of variants in ancestry-specific populations, along with clinical variant analysis and interpretation, are critical to determine their true significance. Methods: Here, we carefully reviewed and classified variants in genes associated with inherited cardiac conditions based on a population whole-genome sequencing cohort of 4810 Singaporeans representing Southeast Asian ancestries. Results: Eighty-nine (1.85%) individuals carried either pathogenic or likely pathogenic variants across 25 genes. Forty-six (51.7%) had variants in causal genes for familial hyperlipidemia, but there were also recurrent variants in SCN5A and MYBPC3 , causal genes for inherited arrhythmia and cardiomyopathy, which, despite previous reports, we determined to lack criteria for pathogenicity. Conclusions: Our findings highlight the incidence of disease-related variants in inherited cardiac conditions and emphasize the value of large-scale sequencing in specific ancestries. Follow-up detailed phenotyping and analysis of pedigrees are crucial because assigning pathogenicity will significantly affect clinical management for individuals and their family members.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

General Medicine

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