Autism Spectrum Disorder is burdened by severely pathogenic variations
within core domains of CHD8 and its CHD7-binding motif
Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder
presented with social and communication deficits, restricted, repetitive
behaviours and interest. Several recurrently mutated genetic
risk-factors have been implicated in ASD manifestation. Chromodomain
helicase remodeller (CHD8) is one such gene that is a master regulator
mediating the expression of genes controlling neuron functions. We
collected 8,124 exonic SNPs in CHD8 from 4 databases representing the
general and ASD populations; subjected them to multi-layered analyses on
>20 computational tools. We observed that nsSNPs were
common in the general population. Distinct hotspots for truncating and
nsSNPs were identified within exons encoding the N and C terminals,
respectively. Evolutionarily conserved regions involving CHD8 core
domains: Helicase-C-terminal, Helicase-ATP-binding and SNF2_N domains,
recorded the lowest density but severely pathogenic SNPs. Conversely,
evolutionarily variable regions- CHD7-binding and BRK domains- hosted
the highest SNPs, but were benign. Post-Translational-Modifications
(PTMS) occurred on residues outside domains (P<0.01) i.e.,
non-conserved regions of CHD8 including the N and C terminals that were
determined to be Intrinsically-Disordered-Protein-Regions (IDPRs) with 9
Molecular-Recognition-Features sites. Contrastingly, ASD population
recorded significantly higher incidences of truncating SNPs than general
population (P<0.0001). ASD-SNPs frequently occurring within
core domains were severely damaging and accounted for >30%
of all ASD variations. The CHD7-DNA-binding motif, with most PTMs,
recorded the highest recurring truncating ASD-SNPs. The CHD8 PPIs
effortlessly recapitulated the phenotypes presented by children with
CHD8 mutations. 11/13 (84.6%) interacting molecules were IDPs. We
identified 9 CHD8 nsSNPs that produced the strongest long-range
disturbances, altering the modelled protein’s global conformational
dynamics.