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

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.

Genetic etiology analysis of 244 fetal ventricular septal defect in the prenatal setting

“…VSDs are openings in the ventricular septum, were associated with genetic factors. In the prenatal setting, about 13-23% of fetuses with VSD have chromosome aneuploidy and CNVs, most of them are trisomy 21, trisomy18, and 22q11 microdeletions [11][12][13]. WES as an additional diagnostic technique beyond traditional methods can added diagnostic yield from 5-20% for CHD [14,15].…”

Clinical Decision Analysis of Genetic Evaluation and Testing in 1013 Intensive Care Unit Infants with Congenital Heart Defects Supports Universal Genetic Testing

“…Despite increasing knowledge of genetic causes of CHD--including chromosomal aneuploidies, chromosome copy-number variation (CNV), and monogenic disorders-genetic testing is underused and screening for genetic disorders is unstandardized [2,[6][7][8][9][10][11][12][13][14][15]. Several recent studies have shown the benefits of Genes 2024, 15, 505 2 of 24 standardizing genetics evaluations in hospitalized patients with CHD [16][17][18][19]. Improving early diagnosis of genetic disorders can inform diagnosis-specific medical management, individual/family risk assessment, and genetic counseling [4,20,21].…”

Approaches to Studying Outcomes in Patients With Congenital Heart Disease With Genetic Syndromes: What Down Syndrome Can Teach Us

“…While some genetic syndromes have a wide spectrum of heterogeneous CHDs, there are a small number of characteristic cardiovascular malformations in DS. 4 This should allow deep phenotyping and more precise estimation of outcome based on lesion type and comorbidities.…”