SETD2関連希少疾患の臨床的洞察：新規バリアントの報告

The SET domain containing the 2 (SETD2) gene encodes a histone methyltransferase responsible for H3K36me3 modification, playing key roles in transcriptional regulation, RNA splicing, and DNA repair. Pathogenic variants in SETD2 have been linked to variable phenotypes, including Luscan-Lumish syndrome (LLS, OMIM #616831), autosomal dominant intellectual developmental disorder 70 (MRD70, OMIM #620157), and Rabin-Pappas syndrome (RAPAS, OMIM #620155). Defining the severity of intellectual disability/developmental delay caused by SETD2 variants is important for accurate genetic counseling. This study aims to present a patient carrying a novel de novo nonsense variant in the SETD2 gene and to expand the clinical phenotype spectrum associated with SETD2 variants. A 17-year-old male with dysmorphic features, epilepsy, attention deficit and hyperactivity disorder (ADHD), and moderate intellectual disability underwent a detailed clinical and genetic evaluation. A novel de novo heterozygous nonsense variant in the SETD2 gene, NM_014159.7:c.7084C>T (NP_054878.5:p.Gln2362Ter), was identified by whole-exome sequencing. This variant was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. The patient exhibited clinical features overlapping with LLS. Further research is warranted to elucidate the mechanistic differences underlying various SETD2 variants, which will be essential for improving our understanding of SETD2-related disorders and for providing accurate genetic counseling and targeted management strategies.