Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FOXP1 : intellectual disability-severe speech delay-mild dysmorphism syndrome

HGNC:3823 | MONDO_0013352
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 14
15.5
12
Hamdan FF et al. 2010 Nov 12 (PMID:20950788); Le Fevre AK et al. 2013 Dec (PMID:24214399); Sollis E et al. 2016 Feb 1 (PMID:26647308); Urreizti R et al. 2018 Jan 12 (PMID:29330474); Johnson TB et al. 2018 Nov 1 (PMID:30385778); Han JY et al. 2018 Dec 17 (PMID:30631761); Lozano R et al. 2015 Dec (PMID:25853299); Song H et al. 2015 Feb (PMID:25767709); Myers A et al. 2017 Dec (PMID:28884888); Bekheirnia MR et al. 2017 Apr (PMID:27657687);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
0.6
0.6
Johnson TB et al. 2018 Nov 1 (PMID:30385778); Worthey EA et al. 2013 Oct 2 (PMID:24083349);
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  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Ferland RJ et al. 2003 May 26 (PMID:12687690);
Functional Alteration Patient cells 1 0 - 2 2
1.5
Non-patient cells 0.5 0 - 1 3 1.5
Sollis E et al. 2016 Feb 1 (PMID:26647308); Meerschaut I et al. 2017 Sep (PMID:28735298); Johnson TB et al. 2018 Nov 1 (PMID:30385778);
Models Non-human model organism 2 0 - 4 4 2 2 3
Usui N et al. 2017 Oct 15 (PMID:29138280); Araujo DJ et al. 2015 Oct 15 (PMID:26494785);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
1
Li X et al. 2015 May 26 (PMID:26010426);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 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 5 17 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
05/09/2019
EXPERT CURATION (DATE)
Definitive
05/09/2019
EVIDENCE SUMMARY
FOXP1 alone was first reported in relation to autosomal dominant intellectual disability-severe speech delay-mild dysmorphism syndrome in 2010 (Carr et al., 20571508; Hamdan et al., 20950788; Horn et al., 20848658). At least 17 unique variants (missense, in-frame indel, 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 19 probands in 12 publications (20571508, 20950788, 20848658, 24214399, 25853299, 24083349, 6647308, 27657687, 28735298, 28884888, 30385778, 29330474). More evidence is available in the literature, but 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, FOXP1 is definitively associated with autosomal dominant intellectual disability-severe speech delay-mild dysmorphism 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 Working Group on 05/09/2019 (SOP Version 6)