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NSD1

nuclear receptor binding SET domain protein 1

The NSD1 gene provides instructions for a protein that acts as a histone methyltransferase, playing a crucial role in gene regulation, growth, and development. The NSD1 gene encodes the nuclear receptor binding SET domain protein 1, which is essential for normal growth and development.

Chromosome 5q35.3 Autosomal dominant HGNC:14234 Tier C
NSD1 5q35.3 p arm q arm 5

NSD1 is located on the long (q) arm of chromosome 5, at band 5q35.3. Arm ratio per GRCh38 - banding schematic.

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Clinical tests that include this

KNOVA NIPT
NSD1 is 1 of 56 genes on this panel
Prenatal NIPT screening (trisomies, microdeletions, single-gene conditions)

Overview

The NSD1 gene, fully known as nuclear receptor binding SET domain protein 1, is crucial for regulating genes involved in human growth and development. It provides instructions for making a protein that functions as a histone methyltransferase, an enzyme that modifies structural proteins called histones [PMID:17962413]. These modifications can alter gene expression, effectively turning genes on or off as needed for proper biological processes. Disruptions in NSD1 function can lead to developmental disorders, most notably Sotos syndrome [PMID:17962413].

What the gene does

The protein produced from the NSD1 gene acts as a histone methyltransferase. This means it adds methyl groups to histones, which are proteins that package DNA into chromosomes. By adding these methyl groups (a process called methylation), the NSD1 protein influences how tightly DNA is wound, thereby controlling the activity of specific genes. This regulation of gene activity is vital for normal cellular functions, particularly during growth and development. Although many specific target genes remain unidentified, the NSD1 protein is understood to govern pathways essential for these developmental processes [PMID:17962413].

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Chromosome location

The NSD1 gene is located on chromosome 5, specifically at position 5q35.3. This genomic location refers to the long (q) arm of chromosome 5, in region 3, band 5, sub-band 3. This region houses genes important for various biological functions.

Protein structure

The NSD1 protein is composed of 2696 amino acids and features several distinct domains. It includes a PWWP 1 domain (amino acids 323-388) and three PHD-type zinc fingers: PHD-type 1 (amino acids 1543-1589), PHD-type 2 (amino acids 1590-1646), and PHD-type 3 (amino acids 1707-1751). Additionally, the protein contains multiple disordered regions scattered throughout its length, including regions at amino acids 207-252, 281-311, 487-514, 872-891, 936-1035, 1067-1093, 1112-1134, 1243-1272, 1294-1344, and 1382-1428, and 1480-1534. The SET domain (amino acids 1942-2059) is crucial for the protein's histone methyltransferase activity, enabling it to modify histones and regulate gene expression. Adjacent to this is the Post-SET domain (amino acids 2066-2082), which further contributes to this function. An AWS domain (amino acids 1890-1940) is also present, and a specific region (amino acids 2060-2066) inhibits enzyme activity when histone is not bound, ensuring precise regulation.

Domain map · 2,696 amino acids
PWWP 1 (323–388)PHD-type 1 (1543–1589)PHD-type 2 (1590–1646)PHD-type 3 (1707–1751)PWWP 2 (1756–1818)AWS (1890–1940)SET (1942–2059)PHD-type 4; atypical (2118–2165)PWWP 1323–388PWWP 21756–1818SET1942–20591~1,3482,696
Domain - independent functional unit
Zinc finger - zinc-binding structural motif
🧬 Explore 3D structure on AlphaFold
UniProt:Q96L73Length:2,696 aaStructure:AlphaFold

Key variants

Variants within the NSD1 gene can range from small changes, such as insertions or deletions of a few DNA bases, to larger genomic rearrangements like deletions affecting the entire gene. These genetic alterations can lead to a non-functional protein or alter its activity, thereby disrupting the normal regulation of growth and developmental genes. The specific type and location of a variant can influence the clinical presentation.

2,655
Total variants catalogued in ClinVar
View all on ClinVar →
702 Pathogenic / Likely pathogenic 946 Uncertain significance 788 Benign / Likely benign 219 Conflicting or other

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.1064-2A>G
single nucleotide variant
 - Pathogenic/Likely pathogenic ★★☆☆ Sotos syndrome
c.1212_1213del
Deletion
 p.Lys405fs Pathogenic ★★☆☆ not provided
c.1318C>T
single nucleotide variant
 p.Arg440Ter Pathogenic ★★☆☆ not provided
c.1397C>G
single nucleotide variant
 p.Ser466Ter Pathogenic ★★☆☆ not provided
c.1492C>T
single nucleotide variant
 p.Arg498Ter Pathogenic ★★☆☆ not provided
c.1583del
Deletion
 p.Lys528fs Pathogenic/Likely pathogenic ★★☆☆ Sotos syndrome
c.1611dup
Duplication
 p.Ile538fs Pathogenic ★★☆☆ Inborn genetic diseases
c.1727dup
Duplication
 p.Asn576fs Pathogenic ★★☆☆ Sotos syndrome
c.1810C>T
single nucleotide variant
 p.Arg604Ter Pathogenic ★★☆☆ not provided
c.1831C>T
single nucleotide variant
 p.Arg611Ter Pathogenic ★★☆☆ not provided

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Pathogenic variants in the NSD1 gene are predominantly associated with Sotos syndrome, an autosomal dominant disorder characterised by overgrowth, distinctive facial features, and learning difficulties. Over 380 different NSD1 mutations have been identified in individuals with Sotos syndrome. While Sotos syndrome is the primary inherited condition, NSD1 gene alterations are also observed in certain cancers, such as childhood acute myeloid leukaemia [PMID:17962413].

  • Sotos syndrome
    Neurogenetics
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Inheritance pattern

Conditions caused by pathogenic NSD1 variants typically follow autosomal dominant inheritance.

♀ Affected parent 1 altered copy ♂ Unaffected parent 2 typical copies Affected Unaffected Unaffected Affected Affected Carrier Unaffected Circles = females · Squares = males

Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.

UK clinical status

The NSD1 gene is included in several expert-curated panels within the UK's NHS Genomic Medicine Service, as listed in PanelApp. These include panels for Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders, childhood solid tumours, congenital hyperinsulinism (R144), DDG2P, early onset or syndromic epilepsy, foetal anomalies (R21), hydrocephalus (R86), intellectual disability, primary lymphoedema (R136), and skeletal dysplasia (R104). This highlights its recognised role in a broad spectrum of paediatric and developmental conditions.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Congenital hyperinsulinism · R144 NHS GMS → Fetal anomalies · R21 NHS GMS → Hydrocephalus · R86 NHS GMS → Primary lymphoedema · R136 NHS GMS → Skeletal dysplasia · R104 NHS GMS → Childhood solid tumours NHS GMS → DDG2P NHS GMS → Early onset or syndromic epilepsy NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Frequently asked questions

What is the main function of the NSD1 gene?

The NSD1 gene provides instructions for creating a protein that acts as a histone methyltransferase. This protein modifies histones, which are structural proteins associated with DNA, thereby regulating gene activity critical for normal growth and development [PMID:17962413].

What condition is most commonly associated with NSD1 gene variants?

The most commonly associated inherited condition with pathogenic variants in the NSD1 gene is Sotos syndrome. This is an autosomal dominant disorder characterised by accelerated growth and developmental challenges.

Can NSD1 gene changes be acquired?

Yes, while germline (inherited) variants in NSD1 cause conditions like Sotos syndrome, somatic (acquired) changes in the gene can also occur. These acquired changes are sometimes found in cancer cells, such as in childhood acute myeloid leukaemia, and are not inherited from parents [PMID:17962413].

References

  1. Kudithipudi S, Lungu C, Rathert P. Substrate specificity analysis and novel substrates of the protein lysine methyltransferase NSD1. Chemistry & biology. 2014. PMID: 24412544
  2. Tatton-Brown K, Rahman N. The NSD1 and EZH2 overgrowth genes, similarities and differences. American journal of medical genetics. Part C, Seminars in medical genetics. 2013. PMID: 23592277
  3. Qiao Q, Li Y, Chen Z. The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. The Journal of biological chemistry. 2011. PMID: 21196496
  4. Pasillas MP, Shah M, Kamps MP. NSD1 PHD domains bind methylated H3K4 and H3K9 using interactions disrupted by point mutations in human sotos syndrome. Human mutation. 2011. PMID: 21972110
  5. Lucio-Eterovic AK, Singh MM, Gardner JE. Role for the nuclear receptor-binding SET domain protein 1 (NSD1) methyltransferase in coordinating lysine 36 methylation at histone 3 with RNA polymerase II function. Proceedings of the National Academy of Sciences of the United States of America. 2010. PMID: 20837538
  6. Berdasco M, Ropero S, Setien F. Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. Proceedings of the National Academy of Sciences of the United States of America. 2009. PMID: 20018718
  7. Wang GG, Cai L, Pasillas MP. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nature cell biology. 2007. PMID: 17589499
  8. Tatton-Brown K, Douglas J, Coleman K. Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. American journal of human genetics. 2005. PMID: 15942875
  9. Faravelli F. NSD1 mutations in Sotos syndrome. American journal of medical genetics. Part C, Seminars in medical genetics. 2005. PMID: 16010675
  10. Kurotaki N, Imaizumi K, Harada N. Haploinsufficiency of NSD1 causes Sotos syndrome. Nature genetics. 2002. PMID: 11896389
  11. Jaju RJ, Fidler C, Haas OA. A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood. 2001. PMID: 11493482
  12. Adam MP, Bick S, Mirzaa GM. Sotos Syndrome. 1993. PMID: 20301652
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 11 October 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .