ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.