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Koen Devriendt

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Open access Aug 2026

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

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.

Molly Godfrey, Michael A. Levy, Christopher Campbell et al. · 0 citations
Open access Jul 2026

Copy number variant analysis by exome sequencing is an effective approach to optimize diagnostic yield for developmental disorders-the DDD-Africa study.

Copy number variants (CNV) contribute significantly to the pathogenic variation associated with developmental disorders. CNV detection is often not included in standard exome sequencing (ES) analysis. Complementary methods such as chromosomal microarray are typically offered in diagnostic laboratories to diagnose pathogenic CNV. In this study, we aimed to develop an effective approach for incorporating CNV detection within our ES analysis process for the Deciphering Developmental Disorders in Africa (DDD-Africa) cohort. We analyzed ES data from 505 probands with a developmental disorder, applying a CNV detection approach that assessed data generated using the tools CANOES and XHMM. When available, parental ES data was used to assess inheritance patterns. We confirmed a diagnosis in 41/505 (8,1%) patients with 43 pathogenic CNV identified in the probands. There were 31 deletions and 12 duplications. Among the 26 probands with parental data, all identified CNV were de novo. The addition of CNV analysis to our ES analysis pipeline resulted in an 8.1% increase in diagnostic yield in the DDD-Africa cohort without additional laboratory cost. This offers a feasible approach which is likely to reduce analytical cost and is suitable for low- and middle-income countries where funding and resources for genomic medicine initiatives are limited.

Nadja Louw, Prince Makay, P. Mpangase et al. · 0 citations