Retrospective analysis and reclassification of DYSF variants in a large French series of dysferlinopathy patients

Charnay, Théo; Blanck, Véronique; Cerino, Mathieu; Bartoli, Marc; Riccardi, Florence; Bonello‐Palot, Nathalie; Nguyen, Karine; Lévy, Nicolas; Gorokhova, Svetlana; Krahn, Martin

doi:10.1038/s41436-021-01164-3

Cited by 16 publications

(15 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the most intractable impediments in investigating rare diseases is the paucity in patient source. In the last decade, nationwide multicenter genetic studies regarding the DYSF gene (Table 1) have been conducted in Italy (Magri et al, 2017), Netherlands (Ten Dam et al, 2019), UK (Klinge et al, 2010), Japan (Izumi et al, 2020), Korea (Shin et al, 2015), and France (Charnay et al, 2021), with 30-250 patients in each but the results lack integration. A previous database-derived study named UMD-DYSF has been conducted in France by analyzing 266 reported DYSF variants in 2012 (Blandin et al, 2012), however, there is no updated comprehensive genetic analysis since then.…”

Section: Introductionmentioning

confidence: 99%

“…Variant ACMG/AMP classifications for the Chinese dysferlinopathy cohortIn the Chinese dysferlinopathy cohort, several standards of the ACMG/ AMP guideline were modified according to the actual situations of the cohort and previous similar studies(Charnay et al, 2021;Dionnet et al, 2020): (1) PVS1 score was assigned in accordance with ClinGen Sequence Variant Interpretation (SVI) recommendations for interpreting the loss of function variants (Abou Tayoun et al, 2018); (2) Since functional studies of the RNA or protein activity were not performed, PS3 score was not applicable; (3) PP3 score was assigned if CADD PHRED score above 25; (4) PM3 score was assigned referring to the SVI Recommendation for in trans Criterion PM3 (Version 1.0); (5) PP1 score was assigned according to the recommendations on recessive disorders by the Hearing Loss ClinGen Working group (Oza et al, 2018); (6) Though protein expression assay was performed in only few patients (Table…”

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective

Zhong

Lin

et al. 2021

Human Mutation

View full text Add to dashboard Cite

Dysferlinopathy is one of the most common subgroup of autosomal recessive limbgirdle muscular dystrophies that is caused by mutations in DYSF gene. However, there is currently no worldwide comprehensive genetic analysis of DYSF variants. Through a national multicenter collaborative effort in China, we identified 222 DYSF variants with 40 novel variants from 245 patients. We then integrated DYSF variants from disease-related genetic databases including LOVD (n = 1020) and Clinvar (n = 1179), to depict the global landscape of disease-related DYSF variants. Normalpopulation-derived DSYF variants from gnomAD (n = 4318) and ChinaMAP (n = 13,330) were also analyzed in comparison. In Chinese patients, gender instead of genotype showed influence on the onset age of dysferlinopathy, with males showing an earlier age of onset. After integrative analysis, we identified two hotspot DYSF mutations, c.2997G>T in world patients and c.1375dup in Chinese patients, respectively. Both the pathogenic and likely pathogenic variants scattered on the whole gene length of DYSF. However, three specific domains (C2F-C2G-TM, DysF, and C2B-Ferl-C2C) contained variants at higher frequencies than reported in both the databases and Chinese patients. This study comprehensively collected available DYSF variant data, which may pave way for genetic counselling and future clinical trial design for gene therapies in dysferlinopathy.

show abstract

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective

Zhong

Lin

et al. 2021

Human Mutation

View full text Add to dashboard Cite

show abstract

“… 38 In addition, a recently published reclassification of DYSF variants in a large French series of patients with dysferlinopathy revealed changed pathogenicity for 17/176 (9.7%) variants. 39 One of the main reasons for the reclassification is the availability of variant frequencies in large population databases (like gnomAD). Further expansion of such databases could help further reclassify some of the variants.…”

Section: Discussionmentioning

confidence: 99%

Alanyl-tRNA Synthetase 1 Gene Variants in Hereditary Neuropathy

Setlere¹,

Jurcenko²,

Gailīte³

et al. 2022

Neurol Genet

View full text Add to dashboard Cite

Background and ObjectivesOur objective was to report 2 novel variants and to reclassify previously reported alanyl-tRNA synthetase 1 (AARS1) variants associated with hereditary neuropathy and to summarize the clinical features of a previously published cohort of patients.MethodsWe performed detailed neurologic and electrophysiologic assessments and segregation analysis of 2 unrelated families with Charcot-Marie-Tooth (CMT) disease with novel variants in the AARS1 gene. Via literature search, we found studies that included neuropathy cases with AARS1 variants; we then reviewed and reclassified these variants.ResultsWe identified 2 CMT families harboring previously unreported likely pathogenic AARS1 variants: c.1823C>A p.(Thr608Lys) and c.1815C>G p.(His605Gln). In addition, we reinterpreted a total of 35 different AARS1 variants reported in cases with neuropathy from the literature: 9 variants fulfilled the current criteria for being (likely) pathogenic. We compiled and summarized standardized clinical and genotypic information for 90 affected individuals from 32 families with (likely) pathogenic AARS1 variants. Most experienced motor weakness and sensory loss in the lower limbs.DiscussionIn total, 11 AARS1 variants can currently be classified as pathogenic or likely pathogenic and are associated with sensorimotor axonal or intermediate, slowly progressive polyneuropathy with common asymmetry and variable age of symptom onset with no apparent involvement of other organ systems.

show abstract

“…All variants were classified according to the ACMG recommendations [ 21 ] adapted to LGMD genes [ 22 ]. Variants in TTN were classified according to the TTN -specific recommendations [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population

Cerino

González‐Hormazábal

Abaji

et al. 2022

Genes

Self Cite

View full text Add to dashboard Cite

Hereditary myopathies are a group of genetically determined muscle disorders comprising more than 300 entities. In Chile, there are no specific registries of the distinct forms of these myopathies. We now report the genetic findings of a series of Chilean patients presenting with limb-girdle muscle weakness of unknown etiology. Eighty-two patients were explored using high-throughput sequencing approaches with neuromuscular gene panels, establishing a definite genetic diagnosis in 49 patients (59.8%) and a highly probable genetic diagnosis in eight additional cases (9.8%). The most frequent causative genes identified were DYSF and CAPN3, accounting for 22% and 8.5% of the cases, respectively, followed by DMD (4.9%) and RYR1 (4.9%). The remaining 17 causative genes were present in one or two cases only. Twelve novel variants were identified. Five patients (6.1%) carried a variant of uncertain significance in genes partially matching the clinical phenotype. Twenty patients (24.4%) did not carry a pathogenic or likely pathogenic variant in the phenotypically related genes, including five patients (6.1%) presenting an autoimmune neuromuscular disorder. The relative frequency of the different forms of myopathy in Chile is like that of other series reported from different regions of the world with perhaps a relatively higher incidence of dysferlinopathy.

show abstract

Retrospective analysis and reclassification of DYSF variants in a large French series of dysferlinopathy patients

Cited by 16 publications

References 19 publications

Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective

Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective

Alanyl-tRNA Synthetase 1 Gene Variants in Hereditary Neuropathy

Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population

Contact Info

Product

Resources

About