Dataset Information

Familial co-occurrence of congenital heart defects follows distinct patterns.

ABSTRACT:

Aims

Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis.

Methods and results

We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes.

Conclusion

Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.

SUBMITTER: Ellesoe SG

PROVIDER: S-EPMC6018923 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:As a rare disease with genetic pathogenesis, observational study about familial CHD recurrence risk on CHD patients with laterality defects is lacking. This study aimed to investigate familial recurrence among families of patients with CHD and laterality defects, and compare them with CHD patients without laterality defects. A total of 184 patients with CHD and laterality defects treated in Cardiovascular Center, Children's Hospital of Fudan University were observed from 2008 to 2019. A detailed family history was documented by trained staff using questionnaires, and information about the subtypes of CHD and laterality defects was also collected. In addition, positive family history information, including all three degrees relatives and all affected family members, was reconfirmed by trained medical staff through face-to-face interviews, telephone interviews, and letter return visits. Of the 184 included patients, 30 had at least one family member (from among three linear generations and distant relatives) with CHD. The familial recurrence rate of CHD in our cohort was 16.3% (30/184), which was higher than the 3.3% (67/2024) of patients with CHD without laterality defects. This result shows that the recurrence rate among the first-, second-, and third-degree relatives was 11.7% (11/94), 1.5% (3/204), and 3.1% (6/91) and that the recurrence rate among siblings (21.4%, 9/42) was higher than that among parents (3.8%, 2/52). The familial recurrence risk of CHD among patients with CHD and laterality defects is high, which is consistent with the previous study that reported a high familial recurrence of heterotaxy of 10%. First-degree relatives have a higher recurrence rate than second- and third-degree relatives, especially siblings. These findings have important significance for prenatal screening, intervention, and genetic counseling in the Chinese population, but may not be generalizable to other populations that may have different rates of familial and sporadic cases.

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