Gene/Disease Pair: | NSD1 : Sotos syndrome |
HGNC:14234 | MONDO_0019349 | |
Mode of Inheritance: | Autosomal dominant inheritance (HP:0000006) |
Expert Panel: | Autism and Intellectual Disability EP |
SOP: | Gene Clinical Validity Standard Operating Procedures (SOP), Version 6 |
Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Points | PMIDs/Notes | |||||
Default | Range | Max | Count | Total | Counted | ||||||
Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 | 7 |
14
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12 |
Douglas J et al. 2003 Jan (PMID:12464997);
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Proband with predicted or proven null variant | 1.5 | 0-2 | 10 | 6 | 3 | 3 |
Kurotaki N et al. 2002 Apr (PMID:11896389); Douglas J et al. 2003 Jan (PMID:12464997); Höglund P et al. 2003 Jan (PMID:12525543);
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Proband with other variant type with some evidence of gene impact | 0.5 | 0-1.5 | 7 |
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Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 |
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Two variants (not predicted/proven null) with some evidence of gene impact in trans | 1 | 0-1.5 | |||||||||
Segregation Evidence | Summed LOD | Family Count | |||||||||
Candidate gene sequencing | |||||||||||
Exome/genome or all genes sequenced in linkage region | |||||||||||
Total Summed LOD Score | |||||||||||
Case-Control Data
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Case-Control Study Type | Case-Control Quality Criteria | Guidelines | Points | PMIDs/Notes | ||||||
Points/Study | Max | Count | Points | Counted | |||||||
Single Variant Analysis | 1. Variant Detection Methodology 2. Power 3. Bias and confounding 4. Statistical Significance |
0-6 | 12 |
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Aggregate Variant Analysis | 0-6 |
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Total Genetic Evidence Points (Maximum 12) | 12 |
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Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Points | PMIDs/Notes | ||||||
Default | Range | Max | Count | Total | Counted | ||||||
Function | Biochemical Function | 0.5 | 0 - 2 | 2 |
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0.5 | |||||
Protein Interaction | 0.5 | 0 - 2 | |||||||||
Expression | 0.5 | 0 - 2 | 1 | 0.5 |
Visser R et al. 2012 Nov 14 (PMID:23155469);
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Functional Alteration | Patient cells | 1 | 0 - 2 | 2 |
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0.5 | |||||
Non-patient cells | 0.5 | 0 - 1 | 1 | 0.5 |
Qiao Q et al. 2011 Mar 11 (PMID:21196496);
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Models | Non-human model organism | 2 | 0 - 4 | 4 | 1 | 0 | 0 |
Migdalska AM et al. 2012 Dec (PMID:22926222);
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Cell culture model | 1 | 0 - 2 | |||||||||
Rescue | Rescue in human | 2 | 0 - 4 |
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Rescue in non-human model organism | 2 | 0 - 4 | |||||||||
Rescue in cell culture model | 1 | 0 - 2 | |||||||||
Rescue in patient cells | 1 | 0 - 2 | |||||||||
Total Experimental Evidence Points (Maximum 6) | 1 |
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Assertion criteria | Genetic Evidence (0-12 points) | Experimental Evidence
(0-6 points) |
Total Points
(0-18) |
Replication Over Time (Y/N) | ||
Description | Case-level, family segregation, or case-control data that support the gene-disease association | Gene-level experimental evidence that support the gene-disease association | Sum of Genetic & Experimental
Evidence |
> 2 pubs w/ convincing evidence over time (>3 yrs) | ||
Assigned Points | =$inputThisData["summary"]["GeneticEvidenceTotal"]?> 12 | =$inputThisData["summary"]["ExperimentalEvidenceTotal"]?> 1 | =$inputThisData["summary"]["EvidencePointsTotal"]?> 13 | YES | ||
CALCULATED CLASSIFICATION | LIMITED | 1-6 | ||||
MODERATE | 7-11 | |||||
STRONG | 12-18 | |||||
DEFINITIVE | 12-18 AND replication over time | |||||
Valid contradictory evidence (Y/N)*
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CALCULATED CLASSIFICATION (DATE) |
Definitive
10/26/2018
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EXPERT CURATION (DATE) |
Definitive
10/26/2018
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EVIDENCE SUMMARY |
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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