Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SLC9A6 : Christianson syndrome

HGNC:11079 | MONDO_0010278
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Rett Angelman EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
8
8
Pescosolido MF et al. 2014 Oct (PMID:25044251);
Proband with predicted or proven null variant 1.5 0-2 10 4.5 4.5
Gilfillan GD et al. 2008 Apr (PMID:18342287); Pescosolido MF et al. 2014 Oct (PMID:25044251);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
1.1
1.1
Gilfillan GD et al. 2008 Apr (PMID:18342287); Garbern JY et al. 2010 May (PMID:20395263);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Strømme P et al. 2011 Nov (PMID:21964919);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 4
Ouyang Q et al. 2013 Oct 2 (PMID:24035762); Xu M et al. 2017 Nov-Dec (PMID:29349289);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
0.5
Ouyang Q et al. 2013 Oct 2 (PMID:24035762);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

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 12 4.5 16.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/02/2018
EXPERT CURATION (DATE)
Definitive
05/02/2018
EVIDENCE SUMMARY
The SLC9A6 gene has been associated with a rare X-linked intellectual disability syndrome known as Christianson syndrome. Clinical features of Christianson syndrome include microcephaly, profound intellectual impairment, global developmental delay, early-onset seizures, absent speech, craniofacial dysmorphism, and hyperkinesis. Christianson syndrome primarily affects hemizygous males, but heterozygous females can be mildly affected (Sinajon et al 2016). The mechanism of disease is loss of function. Missense and truncating variants in the SLC9A6 gene have been reported in Christianson syndrome patients, and variants have either arisen de novo or been inherited from a mildly affected mother. Two distinct mouse models lacking the SLC9A6 gene have had phenotypic features consistent with Christianson syndrome (Ouyang et al 2013, Xu et al 2017). In summary, SLC9A6 is definitively associated with Christianson syndrome in an X-linked manner. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More information can be found at GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK475801/)