DOI: 10.1002/ajmg.a.63503 ISSN: 1552-4825

A severe neurocognitive phenotype caused by biallelic CHD3 variants in two siblings

Racheli Goldfarb Yaacobi, Rivka Sukenik Halevy
  • Genetics (clinical)
  • Genetics


CHD3 heterozygous variants are associated with Snijders Blok‐Campeau syndrome (SBCS) which consists of intellectual disability (ID), macrocephaly, and dysmorphic facies. Most reported variants are missense or loss of function clustered within the ATPase/helicase domain of the protein. We report a severe neurocognitive phenotype caused by biallelic CHD3 variants in two siblings, each inherited from a mildly affected parent. Male and female siblings were referred to the Genetics Clinic due to severe ID and profound dysmorphism. The parents are first cousins of Iranian descent with borderline intellectual abilities. Exome sequencing was performed for the affected female and her parents. A single homozygous candidate variant in the CHD3 gene was detected in the proband: c.5384_5389dup. p.Arg1796_Phe1797insTrpArg, resulting in an in‐frame insertion of 2 amino acids located outside the ATPase/helicase domain at the C‐terminal region of CHD3‐encoding residues. This variant is classified as likely pathogenic according to ACMG guidelines. The variant was detected in a heterozygous state in each parent. Both affected siblings were homozygous, while their unaffected brother did not carry the variant. Biallelic CHD3 variants cause a severe neurodevelopmental syndrome that is distinguishable from SBCS. We assume that the variant type (in‐frame insertion) and location may enable CHD3 biallelic variants.

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