Critical exon indexing improves clinical interpretation of copy number variants in neurodevelopmental disorders

Abstract

ObjectiveTo evaluate a new tool to aid interpretation of copy number variants (CNVs) in individuals with neurodevelopmental disabilities.MethodsCritical exon indexing (CEI) was used to identify genes with critical exons (CEGs) from clinically reported CNVs, which may contribute to neurodevelopmental disorders (NDDs). The 742 pathogenic CNVs and 1,363 variants of unknown significance (VUS) identified by chromosomal microarray analysis in 5,487 individuals with NDDs were subjected to CEI to identify CEGs. CEGs identified in a subsequent random series of VUS were evaluated for relevance to CNV interpretation.ResultsCEI identified a total of 2,492 unique CEGs in pathogenic CNVs and 953 in VUS compared with 259 CEGs in 6,965 CNVs from 873 controls. These differences are highly significant (p < 0.00001) whether compared as frequency, average, or normalized by CNV size. Twenty-one percent of VUS CEGs were not represented in Online Mendelian Inheritance in Man, highlighting limitations of existing resources for identifying potentially impactful genes within CNVs. CEGs were highly correlated with other indices and known pathways of relevance. Separately, 136 random VUS reports were reevaluated, and 76% of CEGs had not been commented on. In multiple cases, further investigation yielded additional relevant literature aiding interpretation. As one specific example, we discuss GTF2I as a CEG, which likely alters interpretation of several reported duplication VUS in the Williams-Beuren region.ConclusionsApplication of CEI to CNVs in individuals with NDDs can identify genes of potential clinical relevance, aid laboratories in effectively searching the clinical literature, and support the clinical reporting of poorly annotated VUS.

Construction of copy number variation landscape and characterization of associated genes in a Bangladeshi cohort of neurodevelopmental disorders

“…Analyses using the “critical-exon” method ( Uddin et al, 2014 , 2016 ) to identify constraint candidate genes discerned a high number of CEGs within the pathogenic variants (7.5) compared to VOUS (0.19) ( p = 0.0002). Moreover, CEGs per pathogenic CNV were also previously reported ( Wassman et al, 2019 ) as reflective of length bias and gene density of pathogenic variants. From the previous studies ( Uddin et al, 2014 ; Uddin et al, 2016 ; Wassman et al, 2019 ), it is observed that critical exon genes are significantly enriched for de novo mutations in autism probands but not in unaffected siblings or in population control subjects.…”

“…Moreover, CEGs per pathogenic CNV were also previously reported ( Wassman et al, 2019 ) as reflective of length bias and gene density of pathogenic variants. From the previous studies ( Uddin et al, 2014 ; Uddin et al, 2016 ; Wassman et al, 2019 ), it is observed that critical exon genes are significantly enriched for de novo mutations in autism probands but not in unaffected siblings or in population control subjects. Identifying critical exon genes has shown ( Wassman et al, 2019 ; Safizadeh Shabestari et al, 2022 ) improvement in clinical interpretations of rare CNVs.…”

“…From the previous studies ( Uddin et al, 2014 ; Uddin et al, 2016 ; Wassman et al, 2019 ), it is observed that critical exon genes are significantly enriched for de novo mutations in autism probands but not in unaffected siblings or in population control subjects. Identifying critical exon genes has shown ( Wassman et al, 2019 ; Safizadeh Shabestari et al, 2022 ) improvement in clinical interpretations of rare CNVs. In this study, CEG analysis of short focal CNVs identified 18 unique CEGs highly expressed in the neurotypical human brain and which have a low burden of non-synonymous variants in the control population.…”

Potential Cross Talk between Autism Risk Genes and Neurovascular Molecules: A Pilot Study on Impact of Blood Brain Barrier Integrity

“…As outlined in Figure 1 , 2037 neurodevelopmental genes [ 29 ] which have links to neurological and developmental abnormalities were included in the dataset. Along with these neurodevelopmental genes, the 594 genes found in the CNVs from clinical subjects were included as the initial dataset (Total = 2631 genes).…”

Clinical Characteristics and Genotype–Phenotype Correlation in Children with KMT2E Gene-Related Neurodevelopmental Disorders: Report of Two New Cases and Review of Published Literature

“…The syndromic cases are often considered to harbor larger genetic defects including copy number variants, whereas nonsyndromic forms are often due to monogenic causes. 5,6 Chromosomal abnormalities are found in around 25% of cases and monogenic causes in up to 10% of cases with developmental disabilities. 1,7,8 Due to widespread availability and increased knowledge of treating physicians after instituting such guidelines, several novel neurodevelopmental disorders have been discovered in recent years.…”