Gene Validity Curation

TBC1D24 - DOORS syndrome

Gene: TBC1D24 (HGNC:29203)
Classification - 03/11/2020
Disease: DOORS syndrome (MONDO_0009079)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hearing Loss
Evidence Summary: Autosomal recessive TBC1D24-related syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness, to benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct phenotypic correlation with pathogenic variant type or location yet, but patterns are emerging (Balestrini 2016). Sensorineural hearing loss is a key feature of DOORS syndrome, which is characterized by deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (Campeau 2014). Isolated seizure disorders without any reported deafness have been seen (Balestrini 2016). In contrast, two of the families reported to have nonsyndromic hearing loss caused by variants in TBC1D24 were shown to have no history of seizures (Rehman 2014). Further, two independent reports identified the same variant in TBC1D24 to be segregating in an autosomal dominant manner with nonsyndromic hearing loss (Azaiez 2014, Zhang 2014). The strength of the evidence that this gene can cause autosomal dominant nonsyndromic hearing loss is Limited, however. Currently there is not enough evidence to treat nonsyndromic hearing loss or isolated seizures as distinct conditions, especially because those affected with DOORS syndrome have both hearing loss and seizure phenotypes. Experimental evidence has implicated a role for the TBC1D24 gene in neuronal development, including neurite length and arborization (Corbett 2010, Falace 2010, Milh 2013) as well as in protection from neuronal oxidative stress (Finelli 2016). While the gene has been shown to be expressed in the murine cochlea (Rehman 2014, Azaiez 2014, Zhang 2014) , there is no further evidence for a potential mechanism of hearing loss. In summary, the TBC1D24 gene is definitively associated with a spectrum of autosomal recessive phenotypes which the Hearing Loss and Epilepsy Gene Curation Expert Panels propose are a spectrum of DOORS syndrome. This classification was approved by both the ClinGen Hearing Loss and Epilepsy Working Groups on 3/19/19 (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 3
4
12
Guven A et al. 2013 Mar (PMID:23343562); Campeau PM et al. 2014 Jan (PMID:24291220);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 21
11.5
Rehman AU et al. 2014 Jan 2 (PMID:24387994); Falace A et al. 2010 Sep 10 (PMID:20727515); Corbett MA et al. 2010 Sep 10 (PMID:20797691); Milh M et al. 2013 Jun (PMID:23526554); Campeau PM et al. 2014 Jan (PMID:24291220); Balestrini S et al. 2016 Jul 5 (PMID:27281533);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 35.65 7
Rehman AU et al. 2014 Jan 2 (PMID:24387994); Falace A et al. 2010 Sep 10 (PMID:20727515); Corbett MA et al. 2010 Sep 10 (PMID:20797691); Balestrini S et al. 2016 Jul 5 (PMID:27281533);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 35.65    
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 2
0.5
1.5
Falace A et al. 2010 Sep 10 (PMID:20727515); Finelli MJ et al. 2016 Feb 5 (PMID:26668325);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Rehman AU et al. 2014 Jan 2 (PMID:24387994); Falace A et al. 2010 Sep 10 (PMID:20727515);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Falace A et al. 2010 Sep 10 (PMID:20727515);
Models Non-human model organism 2 0 - 4 4 2 2 2
Falace A et al. 2014 Feb 11 (PMID:24469796); Fernandes AC et al. 2014 Nov 24 (PMID:25422373);
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) 4

 


 

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 4 16 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
03/11/2020
EXPERT CURATION (DATE)
Definitive
03/11/2020
EVIDENCE SUMMARY
Autosomal recessive TBC1D24-related syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness, to benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct phenotypic correlation with pathogenic variant type or location yet, but patterns are emerging (Balestrini 2016). Sensorineural hearing loss is a key feature of DOORS syndrome, which is characterized by deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (Campeau 2014). Isolated seizure disorders without any reported deafness have been seen (Balestrini 2016). In contrast, two of the families reported to have nonsyndromic hearing loss caused by variants in TBC1D24 were shown to have no history of seizures (Rehman 2014). Further, two independent reports identified the same variant in TBC1D24 to be segregating in an autosomal dominant manner with nonsyndromic hearing loss (Azaiez 2014, Zhang 2014). The strength of the evidence that this gene can cause autosomal dominant nonsyndromic hearing loss is Limited, however. Currently there is not enough evidence to treat nonsyndromic hearing loss or isolated seizures as distinct conditions, especially because those affected with DOORS syndrome have both hearing loss and seizure phenotypes. Experimental evidence has implicated a role for the TBC1D24 gene in neuronal development, including neurite length and arborization (Corbett 2010, Falace 2010, Milh 2013) as well as in protection from neuronal oxidative stress (Finelli 2016). While the gene has been shown to be expressed in the murine cochlea (Rehman 2014, Azaiez 2014, Zhang 2014) , there is no further evidence for a potential mechanism of hearing loss. In summary, the TBC1D24 gene is definitively associated with a spectrum of autosomal recessive phenotypes which the Hearing Loss and Epilepsy Gene Curation Expert Panels propose are a spectrum of DOORS syndrome. This classification was approved by both the ClinGen Hearing Loss and Epilepsy Working Groups on 3/19/19 (SOP Version 6).