KMT2B – Intellectual Developmental Disorder, Autosomal Dominant 68

Heterozygous pathogenic variants in KMT2B, encoding a histone H3 lysine 4 methyltransferase, cause a spectrum of neurodevelopmental phenotypes classified as Intellectual Developmental Disorder, Autosomal Dominant 68 (MRD68). Since its initial description in 2016, over 100 distinct KMT2B variants have been reported in unrelated individuals, with more than 80 % eventually developing dystonia but a subset presenting primarily with cognitive impairment and growth failure (PMID:38425714). Clinical presentation often includes delayed speech, microcephaly, failure to thrive and joint hyperlaxity during early childhood, and variable emergence of movement disorders.

Inheritance follows an autosomal dominant pattern with disease-causing variants predominantly arising de novo. Reported variants span nonsense, frameshift, splice site and missense changes consistent with loss-of-function. In the index case, a 4-year-old girl of Jewish-Israeli descent without dystonia carried a de novo NM_014727.3:c.12_24dup (p.Ser9GlyfsTer?) variant, identified through DNA methylation episignature analysis enabling early definitive diagnosis (PMID:38425714). No additional segregating relatives were reported in this family.

The variant spectrum in MRD68 is dominated by truncating mutations predicting haploinsufficiency, including frameshifts and premature stop codons. Missense variants occur less frequently and often localize to conserved functional domains. To date, no recurrent founder alleles have been defined, underscoring the de novo nature of most pathogenic changes.

Functional studies using genome-wide DNA methylation profiling have established a robust episignature for KMT2B haploinsufficiency. In vitro and ex vivo assays demonstrate that heterozygous loss of KMT2B alters promoter and regulatory region methylation patterns, correlating with impaired gene transcription during neurodevelopment. Episignature analysis has been used to reclassify missense variants of uncertain significance and guide clinical management.

No conflicting evidence disputing the association with MRD68 has been reported. The coherent genetic and epigenetic findings support a haploinsufficiency mechanism. Additional large-scale cohort studies and functional assays will further refine variant interpretation and genotype–phenotype correlations.

Key Take-home: KMT2B loss-of-function variants cause autosomal dominant intellectual developmental disorder, and DNA methylation episignature testing provides a powerful diagnostic adjunct enabling early and accurate classification of pathogenic alleles.

References

• Frontiers in genetics • 2024 • Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report. PMID:38425714

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