Gene Validity Classification Summary

Gene/Disease Pair:

SIX1 : branchio-oto-renal syndrome

HGNC:10887 | MONDO_0007029
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss EP
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 13
6.25
6.25
Ruf RG et al. 2004 May 25 (PMID:15141091); Kochhar A et al. 2008 Apr (PMID:18330911); Noguchi Y et al. 2011 Apr (PMID:21254961); Sanggaard KM et al. 2007 Nov (PMID:17637804); Unzaki A et al. 2018 May (PMID:29500469); Mosrati MA et al. 2011 Sep-Oct (PMID:21700001); Mutai H et al. 2013 Oct 28 (PMID:24164807);
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 1.5 1.5  
Candidate gene sequencing 13.26 4
Ruf RG et al. 2004 May 25 (PMID:15141091); Kochhar A et al. 2008 Apr (PMID:18330911); Sanggaard KM et al. 2007 Nov (PMID:17637804);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 13.26    
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) 7.75
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
0.5
1.5
Ruf RG et al. 2004 May 25 (PMID:15141091);
Protein Interaction 0.5 0 - 2 2 0.5
Ruf RG et al. 2004 May 25 (PMID:15141091); Patrick AN et al. 2009 Jul 31 (PMID:19497856);
Expression 0.5 0 - 2 1 0.5
Zheng W et al. 2003 Sep (PMID:12874121);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 3 1
Ruf RG et al. 2004 May 25 (PMID:15141091); Patrick AN et al. 2009 Jul 31 (PMID:19497856);
Models Non-human model organism 2 0 - 4 4 2 3 3
Bosman EA et al. 2009 Apr 15 (PMID:19389353); Zheng W et al. 2003 Sep (PMID:12874121);
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) 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 7.75 5.5 13.25 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
10/02/2018
EXPERT CURATION (DATE)
Definitive
06/22/2017
EVIDENCE SUMMARY
The association between the SIX1 gene and autosomal dominant branchio-oto-renal syndrome (AD BOR) has been classified as Definitive using the ClinGen Cllinical Validity Framework as of 11/21/16. The first case was published in 2004 by Ruf et al. Some affected individuals do not have any renal phenotype, and are sometimes considered to have branchio-otic syndrome. Mutai 2013 reported a mother and child with the p.Arg110Trp variant in SIX1, which was previously reported in a family with BOR syndrome, who did not have any other clinical features of BOR other than hearing loss. The association with nonsyndromic hearing loss, however, has not been replicated. In a family reported by Salam et al. 2000 with linkage to a novel autosomal dominant nonsyndromic hearing loss locus DFNA23, Ruf 2004 later identified a missense variant in SIX1, but also that an affected individual had progressive renal failure, indicating this family may have actually had BOR syndrome. Functional studies indicate that SIX1 interacts with EYA1, the most common cause of BOR syndrome, and that pathogenic variants in SIX1 impair the protein's ability to bind EYA1 or to bind DNA (Ruf et al. 2004, Patrick et al. 2009) and two mouse models of BOR syndrome have been generated (Zheng et al. 2003, Bosman et al. 2009). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern for BOR and autosomal dominant nonsyndromic hearing loss. Therefore, all of the disease entitites have been lumped into one disease entity, AD BOR. In summary, SIX1 is definitively associated with AD BOR. This classification was approved by the ClinGen Hearing Loss Working Group on 6/22/2017.