Abstract
BackgroundIntellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients.MethodsWe conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches.ResultsWe verified de novo pathogenic single nucleotide variants (SNV) in ARID1B c.1595delG and PHF6 c.820C > T, potentially causative de novo two base indels in SQSTM1 c.115_116delinsTA and UPF1 c.1576_1577delinsA, and de novo SNVs in CACNB3 c.1289G > A, and SPRY4 c.508 T > A, of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including de novo genome assembly. We confirmed a likely contributory 165 kb de novo heterozygous 1q43 microdeletion missed by clinical microarray. The de novo assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation.ConclusionThis study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses.
Highlights
Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment
De novo single nucleotide variants (SNV) identified by objective molecular pathway-based filtration Genes with functional rare de novo SNVs were screened using three pathway analyses programs
Except ARID1B and PHF6, the other genes are novel for ID
Summary
Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients. A significant proportion of ID is caused by genetic defects, yet despite extensive testing including by clinical chromosomal microarray (CMA), ~30% of cases remain idiopathic [1]. Whole exome sequencing (WES) is limited by poor ability or inability to detect non-coding and structural variation, and capturing less than 100% of the exome [2]. Whole genome sequencing (WGS) offers a comprehensive screen of a variety of DNA variation types. Current evidence suggests WGS is able to detect coding variants in 42% of cases missed by WES [2]
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