Interpreting the impact of noncoding structural variation in neurodevelopmental disorders

Abstract

The emergence of novel sequencing technologies has greatly improved the identification of structural variation, revealing that a human genome harbors tens of thousands of structural variants (SVs). Since these SVs primarily impact noncoding DNA sequences, the next challenge is one of interpretation, not least to improve our understanding of human disease etiology. However, this task is severely complicated by the intricacy of the gene regulatory landscapes embedded within these noncoding regions, their incomplete annotation, as well as their dependence on the three-dimensional (3D) conformation of the genome. Also in the context of neurodevelopmental disorders (NDDs), reports of putatively causal, noncoding SVs are accumulating and understanding their impact on transcriptional regulation is presenting itself as the next step toward improved genetic diagnosis.

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

“…In accordance to “Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition” 2 (DSM‐5), NDD encompasses intellectual developmental disorders, communication disorders, autism spectrum disorders, attention‐deficit/hyperactivity disorders, specific learning disorders, and motor disorders 2 . Furthermore, patients with NDDs often demonstrate additional, (non‐) neurological comorbidities 3 …”

Novel Compound Heterozygous Mutation in TRAPPC9 Gene: The Relevance of Whole Genome Sequencing

“…Therefore, it is not surprising that both de novo and inherited SVs are frequently linked to the pathogenesis of NDDs such as ASD, ID, SZ and developmental delay. However, the overall contribution of SV effects in disease etiology is still unclear [9].…”

A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome

“…Altogether, our explorative in silico analysis raises interest with regards to different potential CNV pathogenic mechanisms interfering with gene expression of protein-coding genes, either through direct copy number alterations of the coding sequence or through interference with lncRNA genes or the 3D genome structure. Our findings ask for experimental validation in future studies, including in vivo and in vitro model systems, expression studies and chromosome conformation capture based analyses such as Hi-C [ 67 , 68 ]. The latter technique has the advantage of allowing both the detection and the interpretation of CNVs [ 69 ].…”

“…The latter technique has the advantage of allowing both the detection and the interpretation of CNVs [ 69 ]. With time, a more complete annotation of both the coding and non-coding genome, and a better understanding of the complex gene regulatory landscape, will aid in estimating the phenotypic consequences of both de novo and (combinations of) inherited variants with smaller individual effects [ 68 ].…”