ClinGen Dosage Sensitivity Curation Page

5q35 recurrent (Sotos syndrome) region (includes NSD1)

  • Curation Status: Complete
  • id: ISCA-37425
  • Date last evaluated: 2014-04-10
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 3


Location Information

  • 5q35.2-q35.3
  • GRCh37/hg19 chr5: 175,728,979-177,047,793
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr5: 176,301,976-177,620,792
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000005.9) ()

Haploinsufficiency phenotype comments:

For an extensive discussion of Sotos syndrome and genotype-phenotype associations between microdeletions and intragenic mutations of NSD1, see GeneReviews: http://www.ncbi.nlm.nih.gov/books/NBK1479/. Per GeneReviews, microdeletions are thought to account for ~50% of Japanese and ~15% of non-Japanese Sotos syndrome cases. For additional information about the frequency, size, and mechanism of microdeletions in individuals with clinical diagnoses of Sotos syndrome, see Tatton-Brown et al. 2005 (PMID: 15805156).

  • Triplosensitivity score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
23599694 Rosenfeld et al. (2013): "12 individuals from 8 families [were] found to have interstitial duplications involving NSD1, ranging in size from 370 kb to 3.7 Mb. All individuals are microcephalic, and height and childhood weight range from below average to severely restricted. Mild-to-moderate learning disabilities and/or developmental delay are present in all individuals, including carrier family members of probands; dysmorphic features and digital anomalies are present in a majority."
23913520 Dikow et al. (2013) report 9 individuals from 5 different families with microduplications of the region 5q35.2q35.3 including NSD1 ranging in size from 0.26 to 2.08 Mb. The authors note that four of their patients and three patients published in previous reports shared a recurrent duplication of 1.5 to approximately 2 Mb in size. The individuals in this set had phenotypic features overlapping those of previously reported cases, including short stature, microcephaly, learning disabilities or mild/moderate intellectual disability, distinctive facial features. Some individuals also displayed behavioral problems, ocular anomalies, and minor hand anomalies. In the cases where the microduplication was inherited, the carrier parent was said to be similarly affected.