Abnormal DNA Methylation Profile Suggests the Extension of the Clinical Spectrum of the SETD2 -Related Disorders to a Syndromic Multiple Tumor Phenotype.

SETD2 has an essential role in epigenetic regulation. SETD2 pathogenic variants cause neurodevelopmental disorders (SETD2-NDDs) that most commonly include various degrees of intellectual disability and behavioral disorders, macrocephaly, brain malformations, and generalized overgrowth. A distinctive DNA methylation episignature has been identified for Luscan-Lumish syndrome. A less common phenotype, denoted SETD2-NDD with multiple congenital anomalies, failure to thrive, and profound intellectual disability, has been reported in association with a particular pathogenic variant (p.Arg1740Trp). To date, about 50 patients have been described in the literature with SETD2 causative variants. We report here an individual with a phenotype distinct from SETD2-NDDs, including normal cognition, distinctive facial features, and multiple tumor histories, including a sacral osteoblastoma at age 7, a benign femoral bone tumor at age 17, a peritoneal pseudomyxoma at age 27, and a hypophyseal macroadenoma and a low-grade optochiasmatic glioma at age 37 years. Trio exome sequencing identified a de novo heterozygous missense variant of unknown significance (p.Ser1658Leu) in the SETD2 gene. DNA methylation study by EpiSign assay confirmed the presence of an episignature profile compatible with SETD2-related disorders. Given the implication of somatic SETD2 variants in benign and malignant tumors, the implication of these SETD2 constitutional variants in tumorigenesis is discussed.