KMT2C – Kleefstra syndrome 2

Heterozygous loss-of-function variants in KMT2C (MLL3) underlie Kleefstra syndrome 2, an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, hypotonia, expressive language delay and distinctive dysmorphisms. The condition results from haploinsufficiency of the H3K4 mono-methyltransferase, leading to deficient chromatin modification and impaired transcriptional regulation.

Genetic evidence includes at least 15 unrelated individuals with de novo truncating variants in KMT2C, predominantly frameshift and nonsense changes upstream of the SET domain, resulting in loss of methyltransferase activity ([PMID:38146907]). A novel de novo heterozygous 11 bp deletion, c.1759_1769del (p.Gln587SerfsTer7), was identified in an affected female with global developmental delay, attention deficit hyperactivity disorder, dyspraxia and short stature ([PMID:38146907]). All reported variants cluster N-terminal to the SET domain, consistent with a loss-of-function mechanism.

Segregation data are limited to de novo occurrences; no multigenerational transmission has been observed. The variant spectrum comprises predominantly frameshift and nonsense mutations; no recurrent founder alleles have been reported to date. Inheritance is strictly autosomal dominant.

Affected individuals present with global developmental delay (HP:0001263), attention deficit hyperactivity disorder (HP:0007018), apraxia (HP:0002186) and short stature (HP:0004322), often accompanied by subtle dysmorphic facial features.

Functional studies support haploinsufficiency as the pathogenic mechanism. Brain-specific KMT2C knockout in mice recapitulates core phenotypes of intellectual disability, social deficits and repetitive behaviors akin to ASD and Kleefstra syndrome 2 ([PMID:37538398]). These models demonstrate that loss of KMT2C methyltransferase activity disrupts neuronal network development and epigenetic regulation.

No conflicting evidence disputing the gene–disease relationship has been reported. The integration of robust de novo variant data and concordant animal model findings establishes a strong clinical validity for KMT2C in Kleefstra syndrome 2.

Key take-home: Truncating KMT2C variants are a definitive diagnostic marker for Kleefstra syndrome 2, with haploinsufficiency of the H3K4 methyltransferase driving neurodevelopmental pathology.

References

• Molecular genetics & genomic medicine • 2024 • A novel 11 base pair deletion in KMT2C resulting in Kleefstra syndrome 2. PMID:38146907
• Frontiers in cell and developmental biology • 2023 • KMT2C knockout generates ASD-like behaviors in mice. PMID:37538398

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