Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FOXP2 : specific language disorder

HGNC:13875 | MONDO_0016226
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Intellectual Disability and Autism
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 4
5
5
Reuter MS et al. 2017 Jan (PMID:27572252); Turner SJ et al. 2013 Sep (PMID:23918746);
Proband with predicted or proven null variant 1.5 0-2 10 3 3.5 3.5
MacDermot KD et al. 2005 Jun (PMID:15877281); Reuter MS et al. 2017 Jan (PMID:27572252);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
0.7
0.7
Reuter MS et al. 2017 Jan (PMID:27572252); Lai CS et al. 2001 Oct 4 (PMID:11586359);
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   Summed LOD Family Count 1 1  
Candidate gene sequencing 3.91 1
Lai CS et al. 2001 Oct 4 (PMID:11586359);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.91    
Case-Control Data
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
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 10.2
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Takahashi K et al. 2003 Jul 1 (PMID:12815709); Lai CS et al. 2003 Nov (PMID:12876151);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Vernes SC et al. 2006 Nov 1 (PMID:16984964);
Models Non-human model organism 2 0 - 4 4 3 3 4
Fujita E et al. 2008 Feb 26 (PMID:18287060); Shu W et al. 2005 Jul 5 (PMID:15983371); Haesler S et al. 2007 Dec (PMID:18052609);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
1
Fujita-Jimbo E et al. 2014 Apr 30 (PMID:24607928);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5.5

 


 

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 10.2 5.5 15.7 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
05/31/2019
EXPERT CURATION (DATE)
Definitive
05/21/2019
EVIDENCE SUMMARY
FOXP2 was first reported in relation to autosomal dominant specific language disorder in 2001 (Lai et al., 11586359). At least 10 unique variants (missense, nonsense, frameshift and large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: Variants in this gene have been reported in at least 12 probands in 4 publications (11586359, 15877281, 23918746, 27572252), including a heterozygous de novo 14kb deletion of FOXP2 exons 12-17 (Reuter et al., 2016; 27572252) that would add an additional 2 points so the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by animal models, expression studies and in vitro functional assays. In summary, FOXP2 is definitively associated with autosomal dominant specific language disorder. 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 Working Group on 05/21/2019 (SOP Version 6)