Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FOXI1 : syndromic genetic deafness

HGNC:3815 | MONDO_0019589
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
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
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
1
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
1
Enerbäck S et al. 2018 Mar (PMID:29242249);
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) 1
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
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 2 2
Hulander M et al. 1998 Dec (PMID:9843211);
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

 


 

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 1 2 3 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
03/12/2019
EXPERT CURATION (DATE)
Limited
02/27/2018
EVIDENCE SUMMARY
The FOXI1 gene has been associated with autosomal recessive hearing loss and renal tubular acidosis using the ClinGen Clinical Validity Framework as of 2/27/2018. This association was made using case-level data only. At least 2 missense variants have been reported in humans. FOXI1 was first associated with this disease in humans in 2017​ (Enerback et al.​). Association is seen in at least 2 probands in 1 publication (29242249). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is unknown. The gene-disease association is supported by a homozygous FOXI1 null mouse (Hulander 1998, 9843211). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, this gene-disease association was split from the FOXI1-EVA association due to phenotypic concordance with the mouse model. The FOXI1 and EVA association has been assessed separately. In summary, there is limited evidence to support the FOXI1 and AR hearing loss and renal tubular acidosis association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/2018.