KMT2C encodes a lysine methyltransferase that is part of the COMPASS complex (complex of proteins associated with SET1) involved in chromatin regulation. The relationship between KMT2C and syndromic intellectual disability (ID) was first reported in 2012 (Kleefstra et al., PMID: 22726846) in one individual from a cohort of patients with features of Kleefstra syndrome, which is characterized by ID, childhood hypotonia, and distinctive facial features. The affected individual harboured a heterozygous nonsense variant of unknown inheritance. Since then, at least eight de novo variants (3 nonsense, 4 frameshift and 1 deletion encompassing the entire gene) have been reported with detailed phenotypic descriptions (PMIDs: 29069077, 29276005). Affected individuals presented with a range of ID, language and motor delay, and mild dysmorphic features, some of which resemble Kleefstra-like facial dysmorphisms; additional features include microcephaly in 6 individuals and childhood hypotonia in 4 individuals. Autism spectrum disorder (ASD) or autistic traits were noted in three males and one female (PMIDs: 29069077, 29276005). Numerous truncating, mostly de novo variants in KMT2C have also been reported in large cohort studies of ASD or ID (PMIDs: 21658581, 27824329, 28263302, 31981491, 33057194). The disease mechanism is haploinsufficiency.
The gene-disease relationship is supported by experimental evidence of KMT2C interactions with proteins in the COMPASS complex implicated in ID (e.g., KMT2D, KDM6A), and by a knockout model of the KMT2C fly ortholog trr showing deficits in short term memory and learning (PMID: 28605393).
In summary, there is definitive evidence to support the relationship between KMT2C and autosomal dominant syndromic intellectual disability. This was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on March 2, 2022 (SOP Version 8).
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