DNMT3A variants were first reported in 2014 in relation to autosomal dominant Tatton-Brown-Rahman syndrome (PMID: 24614070), which is characterized by tall stature, distinctive facial gestalt, and intellectual delay. In 2019, Heyn et al. (PMID: 30478443) described three unrelated probands with a reciprocal phenotype characterized by pre- and post-natal proportionate extreme growth restriction with microcephaly, and global developmental delay, now termed Heyn-Sproul-Jackson syndrome (HESJAS). While haploinsufficiency is believed to be the mechanism behind the Tatton-Brown-Rahman syndrome phenotype, the two missense variants currently reported by Heyn et al. are thought to be acting via a gain of function mechanism (PMID:30478443). The split curation for Tatton-Brown-Rahman overgrowth syndrome is assessed separately. Two adjacent variants (W330R and D333N) in three unrelated probands (PMID:30478443) are included in this curation. Neither variant is present in gnomAD. In vitro functional expression studies demonstrated that both W330R and D333N substitutions likely impair DNMT3A’s binding of methylated histone peptides (PMID:30478443).
There is evidence of a gain-of-function mechanism of pathogenicity. Analysis of patient-derived fibroblasts and peripheral blood leukocytes showed that the variants altered chromatin binding specificity leading to significant DNA hypermethylation of multiple genes (PMID:30478443). Finally, mouse models harboring these heterozygous variants recapitulated the human phenotype with reduced brain size, and body weight compared to controls(PMID: 30478443).
In summary, there is limited evidence to support the relationship between DNMT3A and Heyn-Sproul-Jackson (HSJ) syndrome. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on June 8, 2023 (SOP Version 9).
DNMT3A variants were first reported in 2014 in relation to autosomal dominant Tatton-Brown-Rahman syndrome (PMID: 24614070), which is characterized by tall stature, distinctive facial gestalt, and intellectual delay. In 2019, Heyn et al. (PMID: 30478443) described three unrelated probands with a reciprocal phenotype characterized by pre- and post-natal proportionate extreme growth restriction with microcephaly, and global developmental delay, now termed Heyn-Sproul-Jackson syndrome. While haploinsufficiency is believed to be the mechanism behind the Tatton-Brown-Rahman syndrome phenotype, the two missense variants reported by Heyn et al. are thought to act via a gain of function mechanism (PMID: 30478443). The split curation for Tatton-Brown-Rahman overgrowth syndrome is assessed separately.
Two adjacent missense variants (W330R and D333N) that have been reported in three unrelated probands in one publication (PMID: 30478443) are included in this curation. All variants occurred de novo and are not present in gnomAD. In vitro functional expression studies demonstrated that both W330R and D333N substitutions likely impair DNMT3A’s binding of methylated histone peptides (PMID: 30478443).
There is evidence of a gain-of-function mechanism of pathogenicity. Analysis of patient-derived fibroblasts and peripheral blood leukocytes showed that the variants altered chromatin binding specificity leading to significant DNA hypermethylation of multiple genes (PMID: 30478443). Additionally, mouse models harboring these heterozygous variants recapitulated the human phenotype with reduced brain size and body weight compared to controls (PMID: 30478443).
In summary, there is limited evidence to support the relationship between DNMT3A and Heyn-Sproul-Jackson syndrome. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 8, 2023 (SOP Version 9).
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