NSD1 – Sotos syndrome

Sotos syndrome is an autosomal dominant overgrowth disorder characterized by prenatal and postnatal overgrowth, macrocephaly, distinctive craniofacial features, advanced bone age, and developmental delay. Haploinsufficiency of NSD1 (HGNC:14234), encoding a histone H3K36 methyltransferase, is the major genetic cause, with mutations and microdeletions accounting for over 90% of clinically diagnosed cases.

Genetic Evidence

Familial segregation of a recurrent missense variant, c.6524G>C (p.Cys2175Ser), was demonstrated in a three-generation family, affecting two children and their mother, confirming autosomal dominant inheritance and co-segregation of NSD1 alteration with Sotos phenotype ([PMID:19545651]). Across multiple studies, 266 NSD1-positive individuals have been reported, including 239 probands with intragenic point mutations, frameshifts, and microdeletions distributed throughout functional domains, and 50 recurring microdeletions mediated by low copy repeats ([PMID:15942875]; [PMID:12464997]).

Functional Evidence

Biochemical assays revealed that Sotos-associated missense mutations in NSD1 PHD domains abrogate binding to methylated H3K4 and H3K9, impairing transcriptional regulation ([PMID:21972110]). In model systems, Drosophila NSD deletion caused larval overgrowth, learning deficits, and ERK pathway deregulation, mirroring human features, while patient-derived iPSC lines carrying NSD1 c.1633delA showed defective differentiation and NSD1 haploinsufficiency effects on chromatin signaling ([PMID:38301425]).

Integration & Conclusion

NSD1 haploinsufficiency via diverse variant classes—including truncating, missense, splice, and deletion alleles—consistently yields the Sotos syndrome phenotype. Robust genetic and functional concordance over two decades establishes a Definitive gene–disease relationship. NSD1 testing informs diagnosis, recurrence risk counseling, and surveillance for associated complications such as tumor susceptibility.

Key Take-home: NSD1 molecular analysis is critical for confirming Sotos syndrome diagnosis, guiding management of overgrowth, developmental support, and cancer surveillance.

References

• American Journal of Human Genetics • 2005 • Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. PMID:15942875
• American Journal of Human Genetics • 2003 • NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. PMID:12464997
• European Journal of Medical Genetics • 2009 • Familial Sotos syndrome caused by a novel missense mutation, C2175S, in NSD1 and associated with normal intelligence, insulin dependent diabetes, bronchial asthma, and lipedema. PMID:19545651
• Human Mutation • 2011 • NSD1 PHD domains bind methylated H3K4 and H3K9 using interactions disrupted by point mutations in human Sotos syndrome. PMID:21972110

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