A Multicenter Analysis of Abnormal Chromosomal Microarray Findings in Congenital Heart Disease

Author:

Landis Benjamin J.1ORCID,Helvaty Lindsey R.1,Geddes Gabrielle C.1,Lin Jiuann‐Huey Ivy2ORCID,Yatsenko Svetlana A.2ORCID,Lo Cecilia W.2ORCID,Border William L.3,Wechsler Stephanie Burns3,Murali Chaya N.45,Azamian Mahshid S.45ORCID,Lalani Seema R.45,Hinton Robert B.6,Garg Vidu7ORCID,McBride Kim L.78ORCID,Hodge Jennelle C.1,Ware Stephanie M.1ORCID

Affiliation:

1. Indiana University School of Medicine Indianapolis IN

2. University of Pittsburgh Pittsburgh PA

3. Emory University School of Medicine Atlanta GA

4. Baylor College of Medicine Houston TX

5. Texas Children’s Hospital Houston TX

6. Cincinnati Children’s Hospital Medical Center Cincinnati OH

7. Nationwide Children’s Hospital The Ohio State University Columbus OH

8. University of Calgary Calgary Canada

Abstract

Background Chromosomal microarray analysis (CMA) provides an opportunity to understand genetic causes of congenital heart disease (CHD). The methods for describing cardiac phenotypes in patients with CMA abnormalities have been inconsistent, which may complicate clinical interpretation of abnormal testing results and hinder a more complete understanding of genotype–phenotype relationships. Methods and Results Patients with CHD and abnormal clinical CMA were accrued from 9 pediatric cardiac centers. Highly detailed cardiac phenotypes were systematically classified and analyzed for their association with CMA abnormality. Hierarchical classification of each patient into 1 CHD category facilitated broad analyses. Inclusive classification allowing multiple CHD types per patient provided sensitive descriptions. In 1363 registry patients, 28% had genomic disorders with well‐recognized CHD association, 67% had clinically reported copy number variants (CNVs) with rare or no prior CHD association, and 5% had regions of homozygosity without CNV. Hierarchical classification identified expected CHD categories in genomic disorders, as well as uncharacteristic CHDs. Inclusive phenotyping provided sensitive descriptions of patients with multiple CHD types, which occurred commonly. Among CNVs with rare or no prior CHD association, submicroscopic CNVs were enriched for more complex types of CHD compared with large CNVs. The submicroscopic CNVs that contained a curated CHD gene were enriched for left ventricular obstruction or septal defects, whereas CNVs containing a single gene were enriched for conotruncal defects. Neuronal‐related pathways were over‐represented in single‐gene CNVs, including top candidate causative genes NRXN3 , ADCY2 , and HCN1 . Conclusions Intensive cardiac phenotyping in multisite registry data identifies genotype–phenotype associations in CHD patients with abnormal CMA.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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