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

Authors

Benjamin J Landis
Lindsey R Helvaty
Gabrielle C Geddes
Jiuann-Huey Ivy Lin
Svetlana A Yatsenko
Cecilia W Lo
William L Border
Stephanie Burns Wechsler
Chaya N Murali
Mahshid S Azamian
Seema R Lalani
Robert B Hinton
Vidu Garg
Kim L McBride
Jennelle C Hodge
Stephanie M Ware

Publication Date

9-19-2023

Journal

Journal of the American Heart Association

DOI

10.1161/JAHA.123.029340

PMID

37681527

PMCID

PMC10547279

PubMedCentral® Posted Date

9-8-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Child, Humans, Heart Defects, Congenital, Heart, Genomics, Heart Ventricles, Microarray Analysis, chromosomal microarray, congenital heart disease, conotruncal defects, genomics, neurodevelopment, Genetics

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.

Comments

Associated Data