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:

Loss of the NSD1 gene alone has been associated with Sotos Syndrome. Please see the separate for the NSD1 gene (ISCA-2889) for a complete description of the evidence supporting haploinsufficiency of the NSD1 gene. 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 triplosensitivity phenotype
PubMed ID Description
23599694 Rosenfield et al., 2013 reported a case of an 8 year old boy (subject 7) with a reverse Sotos phenotype. The subject had a 365kb gain, arr[hg18]5q35.2q35.3(176395876-176761282)x3, which was maternally inherited. His mother had a possible learning disability (LD). The subject's brother was not tested but had LD, and behavioral problems. This gain on 5q35 encompassed 10 genes, including NSD1.
23913520 Dikow et al. (2013) reported 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 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.
24819041 Novara et al 2014 reviewed cases with 5q35 microduplication encompassing NSD1 gene. It has been reported so far in 27 cases presenting with delayed bone age, microcephaly, failure to thrive and seizures in some cases. They also depict the clinical presentation of three new cases with 5q35 microduplication outlining a novel syndrome characterized by microcephaly, short stature, and developmental delay. Also, in some cases there was delayed bone maturation, without any typical facial or osseous anomalies. All of the reported microduplications encompass multiple genes in addition to NSD1.

Triplosensitivity phenotype comment:

The microduplication of this 5q35.2q35.3 region encompassing NSD1 gene, is associated with what has been described as a "reversed" Sotos syndrome phenotype, commonly including short stature, microcephaly, delayed bone age, and Developmental Delay/Intellectual Disability (DD/ID). A comparison of the smallest duplication includes the entire NSD1 gene to the individual with larger duplications that only partially overlaps NSD1 suggests that whole-gene duplication of NSD1 in and of itself may be sufficient to cause the growth restriction and other phenotypes seen in these patients. PMID: 27172843 J Sachwitz et al., 2017 detected a dup5p35 (383 kb), arr[hg19]5q35.2q35.3(176,446,622?176,829,453)?3, de novo, in one Silver?Russell syndrome (SRS) patient. The genes encompassed are the same with Rosenfield et al subject 7, except plus one small reference gene F12. PMID: 28128410 F G Reis et al., 2017 reported one patient with a de novo 450 kb microduplication at 5q35.2q35.3 by chromosomal microarray, containing NSD1, which resulted in a Sotos syndrome reversed phenotype. PMID: 30774825 Park et al., 2018 reported a 42-year-old male with intellectual disability and unexplained pancytopenia. The chromosomal microarray revealed a 3.46 Mb microduplication at the 5q35.2-q35.3 site including NSD1. PMID: 21998857 Kasnauskiene et al 2011 reported an individual presenting with a Sotos syndrome phenotype with a 5q35.5 duplication overlapping the distal end of subject 7's duplication region (PMID: 23599694). The mechanism through which this duplication may be interfering with NSD1 expression remains to be determined, but combining this report with subject 8's phenotype makes it less likely that duplication of the genes distal to NSD1 are responsible for growth retardation. This leaves 3 genes uniquely duplicated in our subjects with growth retardation: ZNF346, FGFR4 and NSD1. Fibroblast growth factor receptor 4 (FGFR4) is a positive regulator of growth (Lazarus et al., 2007), so it is an unlikely candidate for causing growth retardation. ZNF346 encodes a zinc finger protein that binds double-stranded RNA, and its overexpression in vitro induces apoptosis (Yang et al., 1999), so this gene could feasibly contribute to growth retardation. However, duplication of the entire NSD1 gene remains a strong candidate for causing growth restriction. It encodes the nuclear receptor-binding SET domain-containing protein 1, a methyltransferase that works on histones to help regulate proper gene expression (Lucio-Eterovic et al., 2010, PMID: 20837538; Wagner and Carpenter, 2012, PMID: 22266761). It is feasible that overexpression of NSD1 could drive expression of its target genes in an opposite pattern from what occurs with NSD1 haploinsufficiency, resulting in an opposite phenotype.