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Wolf-Hirschhorn syndrome (MONDO:0008684) is a contiguous gene deletion disorder caused by hemizygous loss of chromosome 4p16.3, characterized by growth deficiency, a "Greek warrior helmet" facies, developmental delay, intellectual disability, and seizures. NSD2 (HGNC:12766), also known as WHSC1 or MMSET, encodes a histone H3 Lys36 methyltransferase located within the critical WHS region.
Heterozygous loss-of-function NSD2 variants have been identified in multiple unrelated individuals with partial or atypical WHS phenotypes. A case series described three de novo truncating variants in unrelated probands presenting with intrauterine growth retardation, global developmental delay, and characteristic facial features (PMID:31171569). Subsequent reports documented de novo frameshift variants such as c.1676_1679del (p.Arg559ThrfsTer38) and c.4029_4030insAA (p.Glu1344LysfsTer49) in children with microcephaly, short stature, failure to thrive, and seizures (PMID:30345613; PMID:31382906). Familial segregation of c.1577dupG (p.Asn527LysfsTer14) in a father and daughter further confirmed autosomal dominant transmission (PMID:33276791).
To date, over 30 unrelated probands harboring heterozygous NSD2 variants have been reported, including frameshift, nonsense, and splice-site changes across functional domains consistent with haploinsufficiency (PMID:29892088). Segregation analysis in one multiplex family demonstrated co-segregation of NSD2 disruption with intellectual disability in two generations (PMID:33276791). These findings establish an autosomal dominant inheritance pattern.
Functional studies substantiate NSD2 haploinsufficiency as the pathogenic mechanism. whsc1-null zebrafish exhibit growth retardation, craniofacial anomalies, neural defects, and swim bladder dysmorphology mirroring WHS findings (PMID:28654864). Genome-edited NSD2 knockin mice and patient-derived induced pluripotent stem cells carrying loss-of-function variants display reduced H3K36 dimethylation and WHS-like DNA methylation signatures (PMID:39669601). Additional assays reveal impaired class switch recombination and disrupted transcriptional regulation by developmental factors, confirming functional concordance with human phenotypes.
No substantive conflicting evidence has been reported. Phenotypic variability appears influenced by the extent of contiguous gene loss, but isolated NSD2 disruptions consistently produce core WHS features without additional contiguous genes.
Integration of extensive genetic, segregation, and robust functional data supports a Definitive ClinGen classification for the NSD2–Wolf-Hirschhorn syndrome association. NSD2 haploinsufficiency should be considered in diagnostic gene panels for WHS-like presentations, and epigenetic profiling may inform future therapeutic approaches.
Key take-home: Heterozygous NSD2 loss-of-function variants cause an autosomal dominant, monogenic form of Wolf-Hirschhorn syndrome through disruption of H3K36 methylation, underpinning both diagnosis and potential epigenetic-targeted interventions.
Gene–Disease AssociationDefinitiveOver 30 unrelated probands with heterozygous NSD2 variants, multigenerational segregation, and concordant functional data Genetic EvidenceStrong
Functional EvidenceStrongZebrafish and mouse models recapitulate WHS features; patient-derived iPSCs and methylation assays confirm NSD2 loss-of-function effects on H3K36me2 and DNA methylation signature ([PMID:28654864]; [PMID:39669601]) |