SET encodes a multifunctional protein involved in transcriptional regulation and chromatin remodeling. The relationship between variants in SET and autosomal dominant intellectual disability (ID) was first reported in 2018 (Stevens et al., PMID: 29688601; Richardson et al., PMID: 29907757). At least 9 variants (5 frameshift, 1 nonsense, 1 splice, 2 missense) have been reported in 10 individuals, with the majority occurring de novo (PMIDs: 25356899, 29688601, 29907757). Affected individuals presented with motor and speech delay, ID and variable additional features, including mild dysmorphic features, microcephaly in two individuals, and autism in one. The gene-disease relationship is further supported by experimental evidence, including interactions with proteins involved in histone modification and encoded by known autosomal dominant ID genes (e.g., CREBBP, CTCF, EP300, KMT2A, SETBP1, RAC1, TREX1) (PMID:29749127), and in vitro studies indicating SET is required for neuronal development (PMIDs: 20800572, 28966118).
In summary, SET is definitively associated with autosomal dominant intellectual disability. This was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 17, 2021 (SOP version 8).
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