Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FTSJ1 : Non-sydromic X-Linked Intellectual Disability

MONDO:0019181 | ORPHA:777 | OMIM:309549
Mode of Inheritance: X-linked inheritance (HP:0001427)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.00
Proband with predicted or proven null variant 1.5 0-2 10 7.00 7
Ramser J et al. 2004 Sep (PMID:15342698); Willems P et al. 1993 Nov (PMID:8288232); Winnepenninckx B et al. 2002 Sep 15 (PMID:12239714); Takano K et al. 2008 Jun 5 (PMID:18081026);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
1.00
1
Hamel BC et al. 1999 Jul 30 (PMID:10398246); Freude K et al. 2004 Aug (PMID:15162322); Guy MP et al. 2015 Dec (PMID:26310293);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
0.00
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
0.00
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
7.00
3  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Ramser J et al. 2004 Sep (PMID:15342698); Hamel BC et al. 1999 Jul 30 (PMID:10398246); Freude K et al. 2004 Aug (PMID:15162322);
3-4.99 1 2
Hamel BC et al. 1999 Jul 30 (PMID:10398246);
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
0.00
Aggregate Variant Analysis 0-6
0.00
Total Genetic Evidence Points (Maximum 12) 11
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.00
0.5
Protein Interaction 0.5 0 - 2 0.00
Expression 0.5 0 - 2 0.50
Freude K et al. 2004 Aug (PMID:15162322);
Functional Alteration Patient cells 1 0 - 2 2
1.00
1
Guy MP et al. 2015 Dec (PMID:26310293);
Non-patient cells 0.5 0 - 1 0.00
Models Non-human model organism 2 0 - 4 4 0.00
Cell culture model 1 0 - 2 0.00
Rescue Rescue in human 2 0 - 4
0.00
Rescue in non-human model organism 2 0 - 4
0.00
Rescue in cell culture model 1 0 - 2 0.00
Rescue in patient cells 1 0 - 2 0.00
Total Experimental Evidence Points (Maximum 6) 1.5

 


 

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 11 1.5 12.5 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
02/12/2018
EXPERT CURATION (DATE)
MODERATE
01/17/2018
The segregation evidence in the curation was provided in two publications. The first publication (PMID: 15342698) in family MRX9 is calculated by GCI with LOD 1.8. The second publication (PMID: 15162322) in family MRX44 has author-generated LOD 2.9 by a previous publication studying the same family (PMID:10398246). Because the two LOD scores calculated were by sequencing of candidate gene, instead of exome/genome or sequencing all genes in the linkage regions, the LOD score should be adjusted according to the revised SOP. The segregation point given to the corrected summed LOD (4.7) should be 1 point. This will bring to total score of the curation to 10.5, which should be categorized as MODERATE.