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

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.

Download Full-text

Prevalence of pathogenic copy number variants among children conceived by donor oocyte

Scientific Reports ◽

10.1038/s41598-021-86242-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sandra Monfort ◽

Carmen Orellana ◽

Silvestre Oltra ◽

Mónica Rosello ◽

Alfonso Caro-Llopis ◽

...

Keyword(s):

In Vitro Fertilization ◽

Copy Number ◽

Assisted Reproductive Technologies ◽

Copy Number Variants ◽

Reproductive Technologies ◽

Significant Excess ◽

Vitro Fertilization ◽

Donor Oocyte ◽

Increased Risk

AbstractDevelopment of assisted reproductive technologies to address infertility has favored the birth of many children in the last years. The majority of children born with these treatments are healthy, but some concerns remain on the safety of these medical procedures. We have retrospectively analyzed both the fertilization method and the microarray results in all those children born between 2010 and 2019 with multiple congenital anomalies, developmental delay and/or autistic spectrum disorder (n = 486) referred for array study in our center. This analysis showed a significant excess of pathogenic copy number variants among those patients conceived after in vitro fertilization with donor oocyte with respect to those patients conceived by natural fertilization (p = 0.0001). On the other hand, no significant excess of pathogenic copy number variants was observed among patients born by autologous oocyte in vitro fertilization. Further studies are necessary to confirm these results and in order to identify the factors that may contribute to an increased risk of genomic rearrangements, as well as consider the screening for genomic alterations after oocyte donation in prenatal diagnosis.

Download Full-text

Congenital heart defects and copy number variants associated with neurodevelopmental impairment

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.62484 ◽

2021 ◽

Author(s):

Tina O. Findley ◽

Alyssa K. Crain ◽

Smridhi Mahajan ◽

Ahmed Deniwar ◽

Jessica Davis ◽

...

Keyword(s):

Congenital Heart Defects ◽

Copy Number ◽

Congenital Heart ◽

Heart Defects ◽

Copy Number Variants ◽

Neurodevelopmental Impairment

Download Full-text

Gene discovery and functional assessment of rare copy-number variants in neurodevelopmental disorders

10.1101/011510 ◽

2014 ◽

Author(s):

Janani Iyer ◽

Santhosh Girirajan

Keyword(s):

Neurodevelopmental Disorders ◽

Copy Number ◽

Molecular Genetic ◽

Copy Number Variants ◽

Fruit Fly ◽

Functional Evaluation ◽

Rare Cnvs ◽

Molecular Genetic Basis ◽

Causal Genes ◽

Genomic Regions

Rare copy-number variants (CNVs) are a significant cause of neurodevelopmental disorders. The sequence architecture of the human genome predisposes certain individuals to deletions and duplications within specific genomic regions. While assessment of individuals with different breakpoints has identified causal genes for certain rare CNVs, deriving gene-phenotype correlations for rare CNVs with similar breakpoints has been challenging. We present a comprehensive review of the literature related to genetic architecture that is predisposed to recurrent rearrangements, and functional evaluation of deletions, duplications, and candidate genes within rare CNV intervals using mouse, zebrafish, and fruit fly models. It is clear that phenotypic assessment and complete genetic evaluation of large cohorts of individuals carrying specific CNVs and functional evaluation using multiple animal models are necessary to understand the molecular genetic basis of neurodevelopmental disorders.

Download Full-text

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

Translational Psychiatry ◽

10.1038/s41398-020-00998-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Diana C. Dima ◽

Rachael Adams ◽

Stefanie C. Linden ◽

Alister Baird ◽

Jacqueline Smith ◽

...

Keyword(s):

Psychiatric Disorders ◽

Copy Number ◽

Genetic Factors ◽

Copy Number Variants ◽

Neural Correlates ◽

Common Mechanism ◽

Node Centrality ◽

Neural Integration ◽

Increased Risk ◽

Theory Framework

Abstract Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal, and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.

Download Full-text