Gene Validity Curation

DYSF - autosomal recessive limb-girdle muscular dystrophy

Gene: DYSF (HGNC:3097)
Classification - 05/01/2020
Disease: autosomal recessive limb-girdle muscular dystrophy (MONDO_0015152)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Limb Girdle Muscular Dystrophy EP
Evidence Summary: The relationship between DYSF and limb girdle muscular dystrophy (LGMD; also known as LGMD 2B, LGMD R2 and generally as dysferlinopathy) inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of April, 2020. This association was made using case-level and experimental data. The DYSF gene is located on chromosome 2p13.2 and encodes multiple transcript variants. The most commonly used transcript is 6.7 kb long with 55 exons encoding a 2080-amino acid protein. More than 200 pathogenic variants reported in humans with autosomal recessive LGMD are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. In addition to ClinVar and LOVD, the UMD-DYSF database hosts an extensive list of DYSF variants (http://www.umd.be/DYSF/W_DYSF/mutation.html). Limb girdle muscular dystrophy is characterized by progressive weakness in muscles including but not limited to the proximal muscles, and affecting the pelvic and shoulder girdle which can lead to difficulty walking or complete loss of ambulation requiring wheelchair use. It is also accompanied by an elevated serum creatine kinase. DYSF has been reported in association with autosomal recessive LGMD as early as 1998 by Liu et al and Bashir et al (PMIDs: 9731526, 9731527). Summary of Case Level Data (12 points): The association is seen in at least 16 probands in 7 publications (PMID: 9731526, 16010686, 21522182, 14678801, 17825554, 16087766, 10196377). Variants in this gene segregated with disease in 8 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease has been reported to be biallelic loss of function. Summary of Experimental Data (6 points): This gene-disease relationship is supported by animal models, expression studies, functional assays and rescue evidence. Dysferlin has a role in sarcolemmal repair and T-tubule organization (PMID: 12736685, 24302765, 28104817). It is strongly expressed in skeletal muscles and localizes to the membrane (PMID: 10196375). Dysferlin has multiple protein interaction partners (PMID: 11532985, 21079765). A number of mouse models (PMID: 23473732, 15254015, 12736685) and rescue in mouse models and patient cells (PMID: 27858744, 20861509, 19834057, 28707952, 31890729, 31019989) are also reported. In summary, the DYSF-autosomal recessive limb-girdle muscular dystrophy gene-disease relationship is definitive. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on 4/14/20 (SOP Version 7). Lumping & Splitting Consideration: OMIM disease entities: Miyoshi muscular dystrophy 1 (254130); Muscular dystrophy, limb-girdle, autosomal recessive 2 (253601); Myopathy, distal, with anterior tibial onset (606768). Variants in DYSF have been described in individuals with additional phenotypes including scapulo-peroneal myopathy, pseudo-metabolic myopathy, asymptomatic hyperCKemia,, and even congenital onset Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities have been lumped into one disease entity, autosomal recessive limb girdle muscular dystrophy (MONDO:0015152).
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 13
24
12
Liu J et al. 1998 Sep (PMID:9731526); Nguyen K et al. 2005 Aug (PMID:16010686); Cacciottolo M et al. 2011 Sep (PMID:21522182); Cagliani R et al. 2003 Dec (PMID:14678801); Leshinsky-Silver E et al. 2007 Dec (PMID:17825554); Vilchez JJ et al. 2005 Aug (PMID:16087766);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
1.5
Liu J et al. 1998 Sep (PMID:9731526); Nguyen K et al. 2005 Aug (PMID:16010686); Cacciottolo M et al. 2011 Sep (PMID:21522182); Cagliani R et al. 2003 Dec (PMID:14678801);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 6.19 1
Weiler T et al. 1999 May (PMID:10196377);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.19    
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 3
0.5
2
Bansal D et al. 2003 May 8 (PMID:12736685); Kerr JP et al. 2013 Dec 17 (PMID:24302765);
Protein Interaction 0.5 0 - 2 2 1
de Morrée A et al. 2010 Nov 5 (PMID:21079765); Matsuda C et al. 2001 Aug 15 (PMID:11532985);
Expression 0.5 0 - 2 2 1
Anderson LV et al. 1999 May (PMID:10196375); Cacciottolo M et al. 2011 Sep (PMID:21522182);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Hofhuis J et al. 2017 Mar 1 (PMID:28104817);
Models Non-human model organism 2 0 - 4 4 2 5 4
Bansal D et al. 2003 May 8 (PMID:12736685); Ho M et al. 2004 Sep 15 (PMID:15254015);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 4
6
Guha TK et al. 2019 Dec 13 (PMID:31890729); Krahn M et al. 2010 Sep 22 (PMID:20861509); Millay DP et al. 2009 Nov (PMID:19834057); Potter RA et al. 2018 July (PMID:28707952);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2 2 2
Dominov JA et al. 2019 Apr (PMID:31019989); Barthélémy F et al. 2015 Sep 2 (PMID:27858744);
Total Experimental Evidence Points (Maximum 6) 6

 


 

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 6 18 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
05/01/2020
EXPERT CURATION (DATE)
Definitive
05/01/2020
EVIDENCE SUMMARY
The relationship between DYSF and limb girdle muscular dystrophy (LGMD; also known as LGMD 2B, LGMD R2 and generally as dysferlinopathy) inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of April, 2020. This association was made using case-level and experimental data. The DYSF gene is located on chromosome 2p13.2 and encodes multiple transcript variants. The most commonly used transcript is 6.7 kb long with 55 exons encoding a 2080-amino acid protein. More than 200 pathogenic variants reported in humans with autosomal recessive LGMD are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. In addition to ClinVar and LOVD, the UMD-DYSF database hosts an extensive list of DYSF variants (http://www.umd.be/DYSF/W_DYSF/mutation.html). Limb girdle muscular dystrophy is characterized by progressive weakness in muscles including but not limited to the proximal muscles, and affecting the pelvic and shoulder girdle which can lead to difficulty walking or complete loss of ambulation requiring wheelchair use. It is also accompanied by an elevated serum creatine kinase. DYSF has been reported in association with autosomal recessive LGMD as early as 1998 by Liu et al and Bashir et al (PMIDs: 9731526, 9731527). Summary of Case Level Data (12 points): The association is seen in at least 16 probands in 7 publications (PMID: 9731526, 16010686, 21522182, 14678801, 17825554, 16087766, 10196377). Variants in this gene segregated with disease in 8 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease has been reported to be biallelic loss of function. Summary of Experimental Data (6 points): This gene-disease relationship is supported by animal models, expression studies, functional assays and rescue evidence. Dysferlin has a role in sarcolemmal repair and T-tubule organization (PMID: 12736685, 24302765, 28104817). It is strongly expressed in skeletal muscles and localizes to the membrane (PMID: 10196375). Dysferlin has multiple protein interaction partners (PMID: 11532985, 21079765). A number of mouse models (PMID: 23473732, 15254015, 12736685) and rescue in mouse models and patient cells (PMID: 27858744, 20861509, 19834057, 28707952, 31890729, 31019989) are also reported. In summary, the DYSF-autosomal recessive limb-girdle muscular dystrophy gene-disease relationship is definitive. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on 4/14/20 (SOP Version 7). Lumping & Splitting Consideration: OMIM disease entities: Miyoshi muscular dystrophy 1 (254130); Muscular dystrophy, limb-girdle, autosomal recessive 2 (253601); Myopathy, distal, with anterior tibial onset (606768). Variants in DYSF have been described in individuals with additional phenotypes including scapulo-peroneal myopathy, pseudo-metabolic myopathy, asymptomatic hyperCKemia,, and even congenital onset Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities have been lumped into one disease entity, autosomal recessive limb girdle muscular dystrophy (MONDO:0015152).