Gene Validity Curation

FGD4 - Charcot-Marie-Tooth disease

Gene: FGD4 (HGNC:19125)
Classification - 04/14/2020
Disease: Charcot-Marie-Tooth disease (MONDO_0015626)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Charcot-Marie-Tooth EP
Evidence Summary: FGD4 was first reported in relation to autosomal recessive Charcot-Marie-Tooth Disease in 2005 (De Sandre-Giovannoli et al., PMID: 15744041), and variant(s) in this gene were associated with Charcot-Marie-Tooth disease in 2007 (Delague et al., 2007; PMID:17564959).Reported cases to date have a childhood onset and are further characterized by very slow motor conduction velocities, and nerve biopsies that show conspicuously folded myelin sheaths. At least 32 unique variants, including missense, nonsense, splice, frameshift, and indels have been reported in humans (Delague et al., 2007; PMID:17564959, Stendel et al., 2007; PMID:17564972, databases the Inherited Neuropathy Variant Database, LOVD, and HGMD) This gene-disease relationship is supported by expression studies and animal models. Investigation determined that FGD4 is ubiquitously expressed in human tissue, and was found to have the highest levels of expression in mouse nerve tissue during the embryonic stage. Additionally, mice with a disruption of FGD4 were found to have dysmyelination in early nerve development and additional myelin abnormalities at later stages of development. Frabin is a guanine nucleotide exchange factor for CDC42, and deleting Fdg4 or Cdc42 in Schwann cells results in a similar defect in myelination, showing that these two genes have an essential function in myelinating Schwann cells. In transfected cells, C-terminal truncations of frabin result in fewer microspikes, which could be a biological assay for investigating FDG4 variants. In summary, FGD4 is DEFINITIVELY associated with autosomal recessive Charcot-Marie-Tooth Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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 5
10
12
Stendel C et al. 2007 Jul (PMID:17564972); Houlden H et al. 2009 Feb 17 (PMID:19221294); Fabrizi GM et al. 2009 Mar 31 (PMID:19332693);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
3
Delague V et al. 2007 Jul (PMID:17564959); Stendel C et al. 2007 Jul (PMID:17564972); De Sandre-Giovannoli A et al. 2005 Mar (PMID:15744041);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 6.97 1
Delague V et al. 2007 Jul (PMID:17564959);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.97    
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
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Delague V et al. 2007 Jul (PMID:17564959); Stendel C et al. 2007 Jul (PMID:17564972);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Stendel C et al. 2007 Jul (PMID:17564972); Horn M et al. 2012 Dec (PMID:23171661);
Models Non-human model organism 2 0 - 4 4 1 3 3
Horn M et al. 2012 Dec (PMID:23171661);
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 12 5.5 17.5 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
04/14/2020
EXPERT CURATION (DATE)
Definitive
04/14/2020
EVIDENCE SUMMARY
FGD4 was first reported in relation to autosomal recessive Charcot-Marie-Tooth Disease in 2005 (De Sandre-Giovannoli et al., PMID: 15744041), and variant(s) in this gene were associated with Charcot-Marie-Tooth disease in 2007 (Delague et al., 2007; PMID:17564959).Reported cases to date have a childhood onset and are further characterized by very slow motor conduction velocities, and nerve biopsies that show conspicuously folded myelin sheaths. At least 32 unique variants, including missense, nonsense, splice, frameshift, and indels have been reported in humans (Delague et al., 2007; PMID:17564959, Stendel et al., 2007; PMID:17564972, databases the Inherited Neuropathy Variant Database, LOVD, and HGMD) This gene-disease relationship is supported by expression studies and animal models. Investigation determined that FGD4 is ubiquitously expressed in human tissue, and was found to have the highest levels of expression in mouse nerve tissue during the embryonic stage. Additionally, mice with a disruption of FGD4 were found to have dysmyelination in early nerve development and additional myelin abnormalities at later stages of development. Frabin is a guanine nucleotide exchange factor for CDC42, and deleting Fdg4 or Cdc42 in Schwann cells results in a similar defect in myelination, showing that these two genes have an essential function in myelinating Schwann cells. In transfected cells, C-terminal truncations of frabin result in fewer microspikes, which could be a biological assay for investigating FDG4 variants. In summary, FGD4 is DEFINITIVELY associated with autosomal recessive Charcot-Marie-Tooth Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.