ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000005.9) (NC_000005.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11896389 Kurotaki et al. (2002) identified 4 different de novo point mutations of NSD1 in 4 of 38 patients with Sotos syndrome. They included a nonsense mutation (1310C->G) in exon 5 which predicted to lead to a truncation of NSD1, and a one-base deletion (3536delA) in exon 5 which leads to a truncation mutation. Also included were a one-base insertion (5998insT) in exon 19 which leads to a truncation mutation, and a base substitution (6151+1G->A) at the splice donor site in intron 20 which confirmed to skip exon 20 and resulting in a truncated protein.
17565729 Saugier-Veber et al. (2007) detected intragenic NSD1 mutations in 83 Sotos syndrome patients by Quantitative Multiplex PCR. Two cases were familial (child-mother). There were 35 nonsense mutations (21 confirmed de novo), 26 frameshift mutations (16 confirmed de novo), 15 missense mutations (10 confirmed de novo), two in-frame deletions (both confirmed de novo), and three splice-site mutations (all confirmed de novo). A total of 48 mutations were novel.
23190751 Sohn et al. 2013 studied 18 patients with Sotos syndrome. Seven of them had NSD1 intragenic variants; two had de novo frameshift variants, one with de novo splice site variant, and three patients with de novo nonsense variants.

Haploinsufficiency phenotype comments:

Loss of NSD1 has been associated with Sotos syndrome (see GeneReviews for additional information). Additional literature evidence includes (but is not limited to): PMIDs 16140999, 19596467, 21677396, 23341071, and 30755392.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

To date, there have been no focal duplications of NSD1, therefore, the gene has a triplosensitivity score of 0. However, duplications of a larger region including this gene have been observed in individuals with what has been described as a "reversed" Sotos Syndrome phenotype. Please see the related region curation "5q35 recurrent (Sotos syndrome) region (includes NSD1) (ISCA-37425) for a full description of the evidence supporting triplosensitivity of this region.