Multiomic Investigation of Shared Genetic Pathways in Paediatric Congenital Heart Disease and Neurodevelopmental Disorders.

A cohort of 14 trios and one duo with NDD and/or CHD was recruited and analysed using whole-genome sequencing, RNA sequencing, and DNA methylation profiling.

• Two probands had both NDD and CHD, two had CHD only, and 11 had NDD only.
• Blood samples were used for all three omic modalities.
• This multiomic approach was designed to investigate shared genetic pathways between CHD and NDD.
• The study design included trios (proband plus both parents) and one duo.

Whole-genome sequencing identified one large chromosomal deletion of approximately 2.5 Mb and seven likely pathogenic or pathogenic (LP/P) variants.

• Two of the seven LP/P variants were in autosomal dominant genes relevant to the patients' phenotypes.
• Five LP/P variants were in autosomal recessive genes, consistent with carrier status.
• The large deletion was approximately 2.5 Mb in size.
• These variants were identified across a cohort of 15 probands with CHD and/or NDD.

A likely pathogenic de novo splice-disrupting variant was identified in the chromatin remodelling gene ARID1B and validated by RNA sequencing.

• ARID1B is a chromatin remodelling gene previously associated with neurodevelopmental phenotypes.
• The variant was classified as likely pathogenic and occurred de novo.
• RNA sequencing was used to validate the splice-disrupting nature of the variant.
• The individual with the ARID1B variant was also among those showing extreme methylation dysregulation.

DNA methylation analysis revealed epigenetic differences between CHD and NDD patients, with CHD patients showing elevated biological age acceleration.

• Biological age acceleration was higher in CHD patients compared to NDD patients.
• Epigenomic profiling was performed using DNA methylation data from blood samples.
• This finding suggests CHD may impose distinct epigenetic burdens compared to NDD alone.
• Both CHD-only and CHD+NDD probands were included in this comparison.

Comparison with a reference cohort of 178 controls identified four probands with extreme methylation dysregulation.

• The reference cohort consisted of 178 controls used as an epigenomic benchmark.
• Four probands showed extreme methylation dysregulation relative to controls.
• One of the four probands with extreme methylation dysregulation was the individual carrying the ARID1B variant.
• This comparison approach enabled identification of outlier epigenetic profiles in the small patient cohort.

Children with congenital heart disease remain at increased risk of co-occurring neurodevelopmental disorders such as ADHD and autism spectrum disorder.

• Prenatal environmental factors including placental dysfunction and altered oxygen levels in utero may contribute to this increased risk.
• Postnatal events such as cardiac surgery may also contribute.
• Shared genetic factors are hypothesised to underlie both conditions.
• Recent medical advances have significantly improved life expectancy for individuals with CHD, making long-term neurodevelopmental outcomes increasingly important.