CHD3 – Snijders Blok-Campeau syndrome

Snijders Blok-Campeau syndrome is an autosomal dominant neurodevelopmental disorder caused by pathogenic variants in the CHD3 gene, which encodes a chromatin remodeling ATPase. First described in 2018, patients present with global developmental delay, intellectual disability, speech and language impairments, hypotonia, and macrocephaly. To date, more than 100 unrelated individuals with de novo or inherited CHD3 variants have been reported (PMID:39542866).

Genetic evidence supports a definitive gene–disease relationship. Over 100 probands have been described with heterozygous missense, frameshift, splice site, or truncating variants clustering in the ATPase/helicase domains (PMID:39542866). Segregation analyses in 21 multiplex families demonstrate cosegregation of CHD3 variants with disease (PMID:35346573). The inheritance mode is autosomal dominant, with both de novo and parental mosaic or inherited cases contributing to disease risk.

The variant spectrum is broad, including recurrent arginine substitutions (e.g., p.Arg1169Trp), canonical splice site changes, and protein-truncating alleles. A prototypical pathogenic splice site variant is c.5590+1G>T, which disrupts normal splicing and is predicted to alter the C-terminal region of CHD3 (PMID:39542866).

Functional assays demonstrate that CHD3 mutations impair ATPase activity and chromatin remodeling. In vitro biochemical studies of helicase domain missense mutations reveal reduced ATP hydrolysis and altered nucleosome repositioning (PMID:30397230). Minigene splicing assays confirm aberrant exon usage for splice variants such as c.1708-1G>T (PMID:39050258). A chd3-knockout zebrafish model replicates characteristic hypersociability and macrocephaly, and metformin treatment rescues behavioral abnormalities (PMID:39988727).

Conflicting evidence arises from variable expressivity in inherited cases; carriers of heterozygous protein-truncating variants may be mildly or not clinically affected, suggesting phenotypic modifiers or reduced penetrance (PMID:35346573). No studies have convincingly refuted the core association.

In summary, CHD3 haploinsufficiency or dominant-negative effects disrupt chromatin remodeling, leading to a consistent neurodevelopmental phenotype. The extensive genetic and functional data over >5 years meet ClinGen criteria for a definitive association. CHD3 testing is clinically useful for diagnosis, genetic counseling, and inclusion in neurodevelopmental disorder panels.

Key Take-home: Pathogenic CHD3 variants cause a definitive, autosomal dominant neurodevelopmental syndrome with characteristic developmental and dysmorphic features, supported by robust genetic and functional evidence.

References

• American journal of medical genetics. Part A • 2025 • Insights From a Novel Splicing Variant and Recurrent Arginine Variants in the CHD3 Gene Causing Snijders Blok-Campeau Syndrome PMID:39542866
• Genetics in medicine : official journal of the American College of Medical Genetics • 2022 • Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome PMID:35346573
• Nature communications • 2018 • CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language PMID:30397230
• Frontiers in genetics • 2024 • Novel genotypes and phenotypes in Snijders Blok-Campeau syndrome caused by CHD3 mutations PMID:39050258
• European journal of human genetics : EJHG • 2025 • Two distinct phenotypes in Snijders Blok-Campeau syndrome and characterization of the behavioral phenotype in a zebrafish model PMID:39988727

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