KDM3B – Diets-Jongmans syndrome

Diets-Jongmans syndrome is an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, short stature, and facial dysmorphism. To date, three unrelated patients have been reported with de novo heterozygous KDM3B variants (PMID:36274669, PMID:36757469).

All three variants are predicted to be loss-of-function or deleterious: a frameshift p.Glu102ValfsTer25 (PMID:36274669), a splice-site variant c.5070> A leading to aberrant transcripts (PMID:36757469), and a missense variant c.2828> A (p.Arg943Gln) (PMID:36757469). No additional affected relatives have been described, supporting a de novo inheritance pattern. A minigene assay for the splice-site variant confirmed disrupted splicing consistent with a truncated protein and loss of demethylase function (PMID:36757469).

Taken together, KDM3B haploinsufficiency is implicated in the pathogenesis of Diets-Jongmans syndrome; however, evidence is limited by the small number of patients. Additional replication and functional studies are needed to establish definitive clinical validity. Key take-home: heterozygous de novo KDM3B variants should be considered in individuals with intellectual disability, short stature, and dysmorphic facial features.

References

• Molecular genetics and metabolism reports • 2022 • A novel de novo pathogenic variant in KDM3B gene at the first Albanian case of Diets-Jongmans syndrome: DIJOS. PMID:36274669
• Neurogenetics • 2023 • Two patients with KDM3B variants and new presentations of Diets-Jongmans syndrome. PMID:36757469

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