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NSD2 – Rauch-Steindl syndrome

Rauch-Steindl syndrome (MONDO:0859219) is an autosomal dominant neurodevelopmental disorder marked by prenatal-onset growth restriction, short stature, global developmental delay, and intellectual disability. Heterozygous de novo loss-of-function variants in NSD2 (HGNC:12766) have been reported in two unrelated patients: a frameshift c.4028del (p.Pro1343GlnfsTer?) identified after DNA methylation episignature analysis in a boy with developmental delay and short stature (PMID:36589751), and a novel truncating variant discovered by whole-exome sequencing in a 7-year-old girl with failure to thrive and hypotonia (PMID:37351323). Both variants arose de novo, were absent from population databases, and confirm NSD2 haploinsufficiency as the underlying genetic mechanism.

Functional assays demonstrate that NSD2 loss-of-function leads to reduced histone H3 lysine 36 dimethylation (H3K36me2) and failure to restore H3K36me2 in knockout cells, as shown by in vitro methyltransferase activity assays (PMID:33941880). Moreover, DNA methylation episignature analysis of patient blood revealed a methylation profile overlapping that of Wolf-Hirschhorn syndrome, underscoring an epigenetic continuum driven by NSD2 haploinsufficiency (PMID:36589751). These data support a dose-sensitive role for NSD2 in growth and neurodevelopment. Key take-home: NSD2 haploinsufficiency should be considered in patients with RAUST-like features to guide accurate molecular diagnosis and management.

References

  • Frontiers in cell and developmental biology • 2022 • Genetically unresolved case of Rauch-Steindl syndrome diagnosed by its wolf-hirschhorn associated DNA methylation episignature. PMID:36589751
  • Frontiers in pediatrics • 2023 • Case report: A de novo NSD2 truncating variant in a child with Rauch-Steindl syndrome. PMID:37351323
  • Genetics in medicine • 2021 • Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype. PMID:33941880

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Two unrelated probands with de novo truncating NSD2 variants in RAUST (PMIDs:36589751;37351323)

Genetic Evidence

Limited

Two de novo truncating NSD2 variants observed in RAUST patients with consistent AD inheritance

Functional Evidence

Moderate

NSD2 loss-of-function variants reduce H3K36me2 activity in vitro and produce RAUST-specific DNA methylation episignature in patient cells (PMIDs:33941880;36589751)