NSD2

Gene Facts

• HGNC Symbol: NSD2 (HGNC:12766)
• HGNC Name: nuclear receptor binding SET domain protein 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: WHSC1
• Alias symbols: MMSET, KMT3G
• %HI: 37.85
• pLI: 1
• LOEUF: 0.14
• Cytoband: 4p16.3
• Genomic Coordinates:

  GRCh37/hg19:	chr4:1873120-1983919
  GRCh38/hg38:	chr4:1871393-1982192

• MANE Select Transcript: NM_001042424.3 ENST00000508803.6
• Function: Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (PubMed:27571355, PubMed:22099308, PubMed:19808676, PubMed:29728617, PubMed:33941880). Also monomethylates nucleosomal histone H3 at 'Lys-36' (H3K36me) in vitro (PubMed:22099308). Does not trimethylate nucleosomal histone H3 at 'Lys-36' (H3K36me3) (PubMed:22099308). However, specifically trimethylates histone H3 at 'Lys-36' (H3K36me3) at euchromatic regions in embryonic stem (ES) cells (By sim... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-4301
• ClinGen Curation ID: CCID:007580
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Related Links:
  4p16.3 terminal (Wolf-Hirschhorn syndrome) region
• Last Evaluated: 10/25/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• syndromic intellectual disability

HI Evidence

• PUBMED: 29760529
  Lozier et al. (2018) reported a de novo heterozygous nonsense variant (p.R1138*) in a male patient with growth retardation, hypotonia, mild intellectual disability, dysmorphic features, and small head circumference. The nonsense variant was identified by whole-exome sequencing and confirmed by Sanger sequencing.
• PUBMED: 30345613
  Boczek et al. (2018) identified a de novo heterozygous frameshift variant (p.Arg559Tfs*38) of NSD2 in a female patient with mild dysmorphic features, intrauterine growth retardation (IUGR), failure to thrive, short stature, developmental delay, and behavioral abnormalities. The features were consistent with a mild form of WHS. The frameshift variant was detected by whole-exome sequencing and confirmed by Sanger sequencing.
• PUBMED: 30244530
  Bernardini et al. (2018) reported three patients with partially overlapping de novo deletions of 4p16.3, ranging in size from 68 kb to 166 kb, involving WHCR1 and/or part of WHSCR2, Patients 2 and 3 had haploinsufficiency of a single gene, NSD2.
• PUBMED: 29892088
  Derar et al. (2019) reported 2 unrelated patients with de novo truncating variants in NSD2 (NM_001042424:c.2518+1G>A and R935*). The clinical phenotypes included IUGR, postnatal growth delay, hypotonia, developmental delay with impaired speech, and variable dysmorphic features, including small head circumference and craniofacial asymmetry.
• PUBMED: 33941880
  Zanoni et al. (2021) reported 18 patients from 16 unrelated families with highly variable clinical phenotypes milder than WHS. The most common features included pre- and postnatal growth retardation; failure to thrive, sometimes with short stature; small head circumference; hypotonia; delayed walking; poor or absent speech; and variably impaired intellectual development, often with learning difficulties or behavioral abnormalities. Most variants (5 missense, 3 nonsense, and 7 frameshift; absent in gnomAD) were de novo, and two were inherited within families. Patients with missense variants were significantly taller and had more frequent behavioral/psychological issues than those harboring truncating variants. In vitro functional expression studies showed that some, but not all, of the tested missense variants caused reduced levels of histone H3 dimethylated at lysine-36 (H3K36me2), impaired NSD2 methylation activity, and were unable to rescue physiologic levels of H3K36me2 in NSD2 knockout cells fully. No functional studies were performed in nonsense and frameshift variants but predicted to result in a loss of function. The authors concluded that the variants decrease or lose NSD2 methyltransferase activity, resulting in the developmental phenotype.
• PUBMED: 35550183
  Wiel et al. (2022) identified a de novo variant of NSD2 (c.2523delG) in a patient with intrauterine growth restriction, low birth weight, neonatal hypotonia, psychomotor delay, muscle hypotrophy, and facial dysmorphism.

• HI Evidence Comments: Deletions of 4p16.3 are associated with contiguous gene deletion syndrome, Wolf-Hirschhorn syndrome (WHS), characterized by distinct facial dysmorphism, growth retardation, developmental delay, intellectual disability, and seizures (OMIM 194190). NSD2 (WHSC1) is located within the 165 kb Wolf-Hirschhorn syndrome critical region. The NSD2 gene encodes a SET domain-containing transcriptional regulatory protein with histone methyltransferase activity associated with actively transcribed genome regions during embryonic development. As a histone methyltransferase, NSD2 is responsible for the methylation of HEK36. Heterozygous loss of function variants, mostly de novo, in the NSD2 gene are associated with autosomal dominant Rauch-Steindl syndrome (RAUST) (OMIM 619695). The clinical features of RAUST include pre- and postnatal growth retardation, short stature and small head circumference, characteristic dysmorphic facial features, and variable developmental delay with delayed motor and speech acquisition and intellectual disability. Additional publications: PMID: 31382906 Jiang et al. (2019) reported a de novo heterozygous frameshift variant (p.Glu1344Lysfs*49) of NSD2 in a male patient with IUGR, feeding difficulties, poor growth, hypotonia, global developmental delay, and dysmorphic features similar to WHS. PMID: 31171569 Barrie et al. (2019) detected de novo variants with maternity and paternity confirmed in 3 unrelated patients (2 nonsense: p.Trp236* and p.Gln265* and 1 frameshift c.1569dupG). The common clinical features included IUGR, short stature, microcephaly, hypotonia, characteristic dysmorphic features, and global developmental delay with language impairment. The authors concluded that de novo loss-of-function variants in the NSD2 gene are pathogenic and contribute to a subset of WHS patients lacking classic phenotypic features. PMID: 33276791 Hu et al. (2020) reported a novel frameshift variant (p.Asn527Lysfs*14) in a daughter and father with overlapping and atypical features of WHS. The daughter had IUGR, growth delay with microcephaly, short stature, mild developmental delay, and dysmorphic features, including hypertelorism. Her father had similar distinct facial features and mild intellectual disability. PMID: 33001864 Murdock et al. (2021) identified a 3.9 kb deletion of exon1 of NSD2, including the transcription start site and the upstream region containing the promoter and enhancer elements, using transcriptome sequencing (RNA-seq). The patient had developmental delay, failure to thrive, unilateral hearing loss, microcephaly, and myopathy. RNA-seq analysis of whole blood and fibroblast data demonstrated reduced expression of NSD2. PCR analysis confirmed that the deletion was not inherited from the mother; however, a paternal sample was unavailable in this study.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: A de novo 560 kb duplication encompassing NSD2 along with other genes was reported in association with intellectual disability and congenital anomalies (PMID:20197130). However, no sole duplication of NSD2 has been reported.