NSD1 encodes a histone methyltransferase. NSD1 was first reported in relation to autosomal dominant Sotos syndrome in 2002 (Kurotaki et al., PMID: 11896389). Sotos syndrome is characterized by overgrowth, distinctive facial features, and intellectual disability. Other major features include autism spectrum disorder, advanced bone age, cardiac and renal anomalies, brain neuroimaging abnormalities, and seizures. 5q35 microdeletions that encompass the entire NSD1 gene are a common cause of Sotos syndrome and tend to be associated with more severe learning disability than intragenic pathogenic variants (PMID: 15942875). Over 300 unique pathogenic variants (including missense, frameshift, nonsense, splice, and large deletions) have been reported in ClinVar.
Eight truncating variants (frameshift, nonsense, and splice) that have been reported in nine probands in two publications (PMIDs: 12464997, 12525543) are included in this curation. Variants usually occur de novo but can be inherited (e.g., PMID: 12525543). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is haploinsufficiency (PMID: 11896389). This gene-disease relationship is also supported by a mouse model and in vitro functional studies.
In summary, there is definitive evidence supporting the relationship between NSD1 and autosomal dominant Sotos syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 26, 2018 (SOP Version 6).
The relationship between NSD1 and Sotos Syndrome (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of 10/15/2018.
Variants in NSD1 were first reported in humans with this disease as early as 2002 (Kurotaki et al. ). Evidence supporting this gene-disease relationship includes case-level and experimental data.
Over 300 unique pathogenic variants (including missense, splicing, nonsense, frameshift and large deletions) have been reported in ClinVar. Variants in this gene have been reported in at least 8 probands in 2 publications (PMIDs 12464997 and 12525543). Variants in this gene usually occur de novo but can be inherited (e.g Hoglund et al 2003). Microdeletions that encompass the entire NSD1 gene are a common cause of Sotos Syndrome and tend to be associated with more severe learning disability than intragenic pathogenic variants (Tatton-Brown et al. 2005).
More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism for disease is haploinsufficiency (Kurotaki et al. 2002).
This gene-disease association is supported by expression studies and in vitro functional assays.
In summary, NSD1 is definitively associated with Autosomal Dominant Sotos Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This classification was approved by the ClinGen ID/Autism Working Group on 10/26/2018.
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