Familial co-occurrence of congenital heart defects follows distinct patterns

Area of Science:

• Cardiovascular Genetics
• Developmental Biology
• Medical Genetics

Background:

• Congenital heart defects (CHD) impact nearly 1% of newborns, with a growing adult population.
• Recurrence patterns and risks of specific malformations in families with CHD are poorly understood, hindering genetic counseling.
• Understanding familial recurrence is vital for clinical decision-making and family planning.

Purpose of the Study:

• To investigate and define recurrence patterns of congenital heart defects (CHD) within families.
• To identify specific co-occurring malformations and their recurrence risks.
• To explore the role of shared genetic factors in familial CHD recurrence.

Main Methods:

• Analysis of 1163 families with 3080 individuals diagnosed with CHD.
• Calculation of concordance and discordance rates for 41 specific malformations.
• Statistical analysis of co-occurrence odds ratios for discordant lesions and comparison with known susceptibility genes.

Main Results:

• Identified distinct groups of cardiac malformations that co-occur within families, indicating shared developmental mechanisms.
• Found that 19% and 20% of co-occurring discordant malformations shared human and mouse susceptibility genes, respectively.
• Demonstrated that rarely co-occurring malformations did not share susceptibility genes, supporting a genetic basis for co-occurrence.

Conclusions:

• Familial CHD exhibits specific recurrence patterns driven by genetically regulated developmental mechanisms.
• The co-occurrence of malformations in families is significantly influenced by shared susceptibility genes.
• These findings have implications for genetic counseling and understanding the etiology of CHD.