Hum Mutat. 2026 Aug 21;2026:7869246. doi: 10.1155/humu/7869246. eCollection 2026.
ABSTRACT
Recent medical advances have significantly improved the life expectancy of individuals with congenital heart disease (CHD); however, these children remain at increased risk of co-occurring neurodevelopmental disorders (NDD), such as attention-deficit/hyperactivity disorder and autism spectrum disorder. Although prenatal environmental factors, including placental dysfunction and altered oxygen levels in utero, as well as postnatal events such as cardiac surgery, may contribute to this increased risk, shared genetic factors may also underlie both conditions. Therefore, this study is aimed at investigating genomic, transcriptomic and epigenomic findings in patients with NDD and/or CHD using an integrative multiomic approach. A cohort of 14 trios and one duo was recruited: Two probands had both NDD and CHD, two had CHD only and 11 had NDD only. Blood samples were analysed using whole-genome sequencing, RNA sequencing and DNA methylation profiling. We identified one large deletion (~2.5 Mb) and seven likely pathogenic/pathogenic (LP/P) variants, including two in autosomal dominant genes relevant to the patients' phenotypes and five in autosomal recessive genes consistent with carrier status. This included a likely pathogenic de novo splice-disrupting variant in the chromatin remodelling gene ARID1B, validated by RNA sequencing. DNA methylation analysis revealed epigenetic differences between CHD and NDD patients, with CHD patients showing elevated biological age acceleration. Comparison with a reference cohort of 178 controls identified four probands with extreme methylation dysregulation, including the individual with the ARID1B variant. Overall, these findings highlight the diagnostic and mechanistic value of integrative multiomic profiling in paediatric developmental disease cohorts.
PMID:42633081 | PMC:PMC13498852 | DOI:10.1155/humu/7869246