Evaluating High-Confidence Genes in Conotruncal Cardiac Defects by Gene Burden Analyses

Area of Science:

• Genetics
• Cardiology
• Genomic Medicine

Background:

• Nonsyndromic conotruncal cardiac defects (CTDs) diagnosis increasingly uses next-generation sequencing (NGS).
• Existing diagnostic gene panels lag behind research findings, highlighting a need for evidence-based gene curation.
• Understanding genetic underpinnings of CTDs is crucial for accurate diagnosis and treatment.

Purpose of the Study:

• To identify novel genes associated with nonsyndromic conotruncal cardiac defects.
• To evaluate the utility of rare and ultrarare variants in diagnosing CTDs.
• To provide evidence for prioritizing genes in clinical diagnostic panels.

Main Methods:

• Exome sequencing data from 245 patients with CTDs were analyzed.
• Burden analysis was performed on a high-confidence congenital heart disease gene list (n=132) using rare (<0.01%) and ultrarare variants.
• Meta-analysis with three published studies (n=1451) and subgroup analysis of Chinese subjects were conducted.

Main Results:

• An excess of rare variants was confirmed in patients compared to controls.
• Two known genes (GATA6, NOTCH1) and four candidate genes (ANKRD11, DOCK6, NPHP4, STRA6) were identified.
• Ultrarare variant analysis highlighted FLT4, NOTCH1, and TBX1; GATA6 was significant in Chinese subjects.

Conclusions:

• Identified genes warrant prioritization for clinical testing of rare inherited and de novo variants in CTDs.
• ClinVar associations for these genes are predominantly variants of uncertain significance.
• Larger, ethnically diverse cohorts are needed for stringent assessment and curation of CTD genes.