Challenges in Diagnosing Congenital Heart Disease: Insights from 100kGP Cohorts
Overview of CHD Participant Cohorts
Table of Contents
In the 100,000 Genomes Project (100kGP), researchers studied 286 syndromic congenital heart disease (sCHD) probands and 262 familial congenital heart disease (fCHD) probands. The analysis included genomes aligned to GRCh37 or GRCh38. Among these, 328 participants were part of trios, with both parental samples available. The cohort represented various heart phenotypes, including:
- Septal defects: 52.4%
- Valvular defects: 40.5%
- Tetralogy of Fallot: 11.2%
- Transposition of the great arteries: 7.7%
Approximately half of the participants had syndromic disease. 77.68% reported one or more non-cardiac features. Only 6.29% of sCHD cases and 3.89% of fCHD cases were classified as solved. Researchers identified 39 likely pathogenic or pathogenic variants and 56 variants of uncertain significance (VUS).
Gene Discovery Pipeline Findings
The gene discovery pipeline (GDP) identified nine heterozygous de novo variants (DNVs) in known genes, comprising eight single nucleotide variants (SNVs) and one structural variant (SV). Seven of these variants were classified as pathogenic or likely pathogenic. Key reasons for missed diagnoses included:
- Exclusion of morbid genes from genetic panels.
- Inclusion of newly identified disease genes not on previous panels.
Notable Genomic Findings in CHD Participants
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Participant #1: A 19-year-old man with Eisenmenger syndrome exhibited a heterozygous de novo missense variant in the MECOM gene, linked to radioulnar synostosis.
- Participant #9: An 8-year-old girl with hypoplastic left heart syndrome (HLHS) was diagnosed with a 2.3 kb de novo deletion in UBE3A, causing Angelman syndrome. This deletion was not detected in earlier analyses due to insufficient probe coverage.
Candidate Gene Prioritization
A total of 79 candidate genes were identified and prioritized based on their expression in the developing mouse heart. The analysis highlighted genes crucial for cardiac development. This list contained genes like Akap13 and Bcar1, which are known to play significant roles in cardiac function.
Assessment of Candidate Variants
In a separate cohort, 12 candidate variants in genes such as HMCN1 and TFAP2C were identified. However, all variants were inherited from unaffected parents, leaving open the possibility of incomplete penetrance.
Conclusion
This study showcases the challenges and successes in identifying genetic causes of congenital heart disease. The contributions from de novo variants and gene prioritization are vital for understanding and potentially diagnosing these complex conditions. Continued research is essential for uncovering additional genetic factors linked to congenital heart disease.