An episignature informed systematic analysis to ascertain the clinical significance and consequences of CHD8 missense variants.

Disease-causing CHD8 missense variants cluster in structured or functional protein domains and produce the episignature already described for truncating variants, supporting a loss- or reduced-function mechanism.

Pathogenic CHD8 variants cause autosomal dominant intellectual developmental disorder with autism and macrocephaly and are among the most common monogenic causes of autism; the clinical significance of missense variants frequently remains uncertain. Systematic application of ACGS/ACMG guidelines to 36 CHD8 missense variants in 39 affected patients classified only two as likely pathogenic, the remaining 34 staying VUS, 14 of them at least tepid by posterior probability of pathogenicity (≥ 50%); comprehensive phenotypic analysis revealed no discernible clinical difference between those carriers and the others, offering no additional insight for classification. EpiSign testing revealed the CHD8-related episignature, as previously detected in patients with truncating or null variants, in 11 cases, allowing 8 VUS — all previously at least tepid — to be reclassified as likely pathogenic. Molecular modelling showed that disease-causing missense variants cluster in structured or functional protein domains; compared with truncating variants they were less often associated with attention issues and macrocephaly, and three were inherited from unaffected or mildly affected parents.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The most instructive result is a negative one: clinical assessment, however detailed, does not separate carriers of tepid VUS from the others, which rules out the phenotype-only approach for this gene. The episignature delivers 8 reclassifications out of 36 variants, a real but partial gain — positive cases are informative, negative ones are not conclusive — and inheritance from unaffected or mildly affected parents is a reminder that incomplete penetrance still blurs interpretation. In practice, faced with a CHD8 missense variant located in a structured domain in a child with a neurodevelopmental disorder and autism, methylation analysis becomes the second-line test to request before concluding.

Analysis by Dr Thibaut Benquey