DNMT3A – Heyn-Sproul-Jackson syndrome

A heterozygous de novo DNMT3A splice‐region variant, c.1012_1014+3del, was identified in a five-year-old girl presenting with microcephaly, craniosynostosis, and profound global developmental delay, consistent with Heyn-Sproul-Jackson syndrome (HESJAS) ([PMID:37303757]). Parental testing confirmed absence of the variant, supporting an autosomal dominant de novo inheritance with no affected relatives.

Limited functional data demonstrate that patients with DNMT3A loss-of-function variants exhibit a haploinsufficient DNA methylation profile, indicative of reduced methyltransferase activity and concordant with the microcephalic phenotype ([PMID:37209493]). These findings contrast with the macrocephalic overgrowth seen in Tatton-Brown-Rahman syndrome, expanding the clinical spectrum of DNMT3A pathogenic variants. Diagnostic screening for DNMT3A should be considered in cases of unexplained microcephaly with craniosynostosis and developmental delay.

References

• Frontiers in Pediatrics • 2023 • A novel pathogenic variant of DNMT3A associated with craniosynostosis: a case report of Heyn-Sproul-Jackson syndrome. PMID:37303757
• Neuromuscular Disorders • 2023 • Expanding the phenotype of DNMT3A as a cause a congenital myopathy with rhabdomyolysis. PMID:37209493

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