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From Overgrowth to Complex Malformations: A Novel EZH2 Variant Reveals the Expanding Clinical Spectrum of Weaver Syndrome

Year: 2025

Type: article

Abstract: Weaver syndrome is a rare congenital overgrowth disorder caused by heterozygous pathogenic variants in EZH2, a gene encoding a histone methyltransferase essential for epigenetic regulation. We describe a 4-year-old Taiwanese female who exhibited classical features of Weaver syndrome, including macrosomia (height and weight >97th percentile), macrocephaly, hypertelorism, prominent forehead, and developmental delay, along with atypical findings of severe bilateral camptodactyly and complex brain malformations. Neuroimaging revealed corpus callosum dysgenesis with rostral agenesis and genu hypoplasia, bilateral frontal lobe hypoplasia, and an arachnoid cyst. The patient had global developmental delay with marked gross and fine motor impairment but relatively preserved speech and cognition. Whole-exome sequencing identified a novel de novo pathogenic variant in EZH2: c.449T>C (p.Ile150Thr). This variant affects a highly conserved amino acid within the SANT domain and is predicted to be deleterious by computational analysis. Its de novo origin was confirmed by Sanger sequencing. This case broadens the clinical spectrum of Weaver syndrome by highlighting severe camptodactyly and complex brain malformations as possible EZH2-related manifestations. The corpus callosum dysgenesis and associated cerebral abnormalities suggest a wider role of EZH2 in neurodevelopment than previously recognized. These findings underscore the importance of comprehensive neuroimaging and molecular genetic testing in patients with suspected Weaver syndrome, particularly in atypical presentations.

Source: Children

DOI: 10.3390/children12111487