Contribution of Congenital Heart Disorders Associated With Copy Number Variants in Mediating Risk for Brain Developmental Disorders: Evidence From 20-Year Retrospective Cohort Study

Abstract

Rare pathogenic copy number variants (CNVs) are genetic rearrangements that have been associated with an increased risk for congenital heart disorders (CHDs). However, the association of CNVs with atypical brain development, leading to neurodevelopmental disorders (NDDs), in the presence of CHDs remains unclear. We attempted to explore this association by establishing the prevalence and burden of CNVs associated with CHD in a Welsh population and by studying the effect of rare CNVs associated with CHDs in mediating the risk of NDDs. Toward this goal, we analyzed data from the Congenital Anomaly Register for Wales (CARIS), referred from hospitals in Wales between 1998 and 2018, which included 1,113 subjects in total. Of these, 785 subjects were included in the study following application of the exclusion criteria, and a total of 28 rare CNVs associated with CHD were analyzed. The findings from this cohort study identified 22q11.2 deletion as the most prominent CNV across the cohort. Our data demonstrates that the survival rate of the cohort after 3 years was 99.9%, and mortality fell significantly between 1 and 2 years and between 2 and 3 years [F(1,27) = 10, p = 0.0027; F(1,27) = 5.8, p = 0.0222]. Importantly, the data set revealed a positive correlation between the incidence of congenital heart disease and the incidence of neurodevelopmental abnormalities in patients with CNVs across the whole cohort [95% CI (0.4062, 0.8449), p < 0.0001, r = 0.6829]. Additionally, we identified significant CNVs that result in the co-morbidity of CHD and NDD and show that septal defects and global developmental delay are major congenital defects. Further research should identify a common molecular mechanism leading to the phenotypic comorbidity of CHDs and NDDs, arising from a common CNV, which can have an implication for improving risk classification and for fetal neuroprotection strategies in the affected children and in precision medicine.

Chromosomal Microarray Analysis in Fetuses Detected with Isolated Cardiovascular Malformation: A Multicenter Study, Systematic Review of the Literature and Meta-Analysis

“…A further 74 articles were secondarily excluded from the quantitative analysis. Of these, 38 did not provide quantitative data [ 6 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ], in 22 articles it was not possible to infer a quantitative analysis of incremental yield of CMA over standard karyotyping [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 …”

The association of neurodevelopmental abnormalities, congenital heart and renal defects in a tuberous sclerosis complex patient cohort

“…The heart and brain development is intimately related, and children with CHDs are well-known to be at increased risk of NDD likely due to altered perfusion and substrate delivery to the developing brain during early gestation [ 50 , 51 ]. Furthermore, significant altered brain metabolism and microstructure as well as white matter immaturity and delay in cortical folding has been noted in CHD individuals shortly after birth [ 52 , 53 ]. Contrary to this, the association between CHD and KD is not as well-established.…”

Translational Study of Copy Number Variations in Schizophrenia

“…CNVs at proximal 16p11.2 are also associated with neurodevelopmental disorder, intellectual disability, attention-deficit hyperactivity disorder, depression, and autism [ 34 , 36 , 47 , 48 , 49 , 50 , 51 ]. Finally, CNVs at 22q11.2 are associated with congenital heart disease, neurodevelopmental disorders, intellectual disability, autism spectrum disorders, and other neuropsychiatric conditions [ 7 , 48 , 52 , 53 ]. Together, these data indicate that clinical manifestations of CNVs at the eight loci in this study are not limited to schizophrenia; they have pleiotropic clinical effects.…”