Gene Validity Classification Summary

Gene/Disease Pair:

FOXI1 : enlarged vestibular aqueduct syndrome

HGNC:3815 | MONDO_0023069
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss 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
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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
0.25
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
0.25
Liu Y et al. 2016 Dec 20 (PMID:27997596);
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) 0.25
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2 0.5
Hulander M et al. 2003 May (PMID:12642503);
Expression 0.5 0 - 2 1
Hulander M et al. 1998 Dec (PMID:9843211); Hochmann S et al. 2007 Jan (PMID:16950663);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1
Yang T et al. 2007 Jun (PMID:17503324); Nissen RM et al. 2003 Jun (PMID:12702667);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
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) 2.5

 


 

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 0.25 2.5 2.75 NO
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)
Limited
09/10/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
09/10/2018
REASON(S) FOR CHANGE
Cases reported by Yang et al 2007 were subsequently disputed. A case reported by Lui et al. 2016 present a proband who only carries a variant on one allele. Additional reported cases provided no evidence for variant pathogenicity.
EXPERT CURATION (DATE)
Disputed
09/10/2018
EVIDENCE SUMMARY
The FOXI1 gene has been associated with autosomal recessive enlarged vestibular aqueduct syndrome using the ClinGen Clinical Validity Framework as of 5/19/17. Association is seen in one proband with a de novo heterozygous missense variant (Liu et al. 2016 27997596). Association was also made in at least 5 probands with missense variants by Yang et al. 2007 (17503324). These associations were subsequently disputed by Choi et al. 2009 (DOI 10.1002/humu.21098). This gene-disease association is supported by expression studies and protein interaction studies. Of note, this gene has also been implicated in hearing loss and renal tubular acidosis​. This been​ assessed separately. In summary, there is convincing evidence disputing the association between FOXI1 and autosomal recessive enlarged vestibular aqueduct syndrome. More evidence is needed to either support or refute the role FOXI1 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/18.