- EpiSign testing identified CHD8-IDDAM episignature in 11 cases, enabling reclassification of eight tepid VUS to likely pathogenic, increasing diagnostic yield.
- Applying ACGS/ACMG criteria to 36 CHD8 missense variants yielded only two likely pathogenic; 34 remained VUS, highlighting persistent classification uncertainty.
- Pathogenic CHD8 missense variants cluster in structured functional domains and likely act by loss or reduced function, with less macrocephaly observed.
Eur J Hum Genet. 2026 Aug 10. doi: 10.1038/s41431-026-02209-4. Online ahead of print.
ABSTRACT
Pathogenic CHD8 variants cause autosomal dominant ‘Intellectual developmental disorder with autism and macrocephaly’ (IDDAM) and are amongst the most common monogenic causes of autism. The clinical significance of CHD8 missense variants (MVs) frequently remains uncertain. Systematically applying ACGS/ACMG guidelines to 36 CHD8 MVs in 39 affected patients, only two variants were classified likely pathogenic (LP), with the remaining 34 classified variants of uncertain significance (VUS). We subclassified the variants according to posterior probability of pathogenicity (PPP), with 14 being at least tepid VUS (PPP ≥ 50%). Comprehensive phenotypic analysis revealed no discernible clinical differences between individuals carrying at least tepid VUS and others, offering no additional insight for variant classification. EpiSign™ testing revealed a CHD8-IDDAM episignature, as previously detected in patients with truncating/null variants, in 11 cases, allowing reclassification of 8 VUS (all previously classified at least tepid) as LP. Molecular modelling indicated that disease-causing (LP/P) CHD8 MVs are concentrated in structured and/or functional protein domains. Compared to truncating/null variants, disease-causing MVs were less often associated with attention issues and macrocephaly, but clinical features were otherwise similar. Additionally, three disease-causing MVs were inherited from unaffected/mildly affected parents. Overall, we show that determining the clinical significance of CHD8 MVs is challenging, even with detailed clinical information, but that incorporating episignature analysis increases diagnostic yield. Further, our results indicate that CHD8 MVs are likely to act via a loss-of-or reduced function mechanism. These findings reveal the importance and complexity of interpreting CHD8 MVs and will improve the diagnosis and understanding of CHD8-related disorders.
PMID:42575949 | DOI:10.1038/s41431-026-02209-4
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