Genotype-phenotype correlation and natural history study of dysferlinopathy: a single-centre experience from India.
Asymptomatic hyperCKemia
Dysferlinopathy
Genotype–phenotype correlation
LGMDR2
Limb-girdle muscular dystrophy
Miyoshi myopathy
Muscular dystrophy
Journal
Neurogenetics
ISSN: 1364-6753
Titre abrégé: Neurogenetics
Pays: United States
ID NLM: 9709714
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
11
10
2022
accepted:
15
12
2022
pubmed:
30
12
2022
medline:
11
1
2023
entrez:
29
12
2022
Statut:
ppublish
Résumé
Dysferlinopathies are a group of limb-girdle muscular dystrophies causing significant disability in the young population. There is a need for studies on large cohorts to describe the clinical, genotypic and natural history in our subcontinent. To describe and correlate the clinical, genetic profile and natural history of genetically confirmed dysferlinopathies. We analysed a retrospective cohort of patients with dysferlinopathy from a single quaternary care centre in India. A total of 124 patients with dysferlinopathy were included (40 females). Median age at onset and duration of illness were 21 years (range, 13-50) and 48 months (range, 8-288), respectively. The average follow-up period was 60 months (range, 12-288). Fifty-one percent had LGMD pattern of weakness at onset; 23.4% each had Miyoshi and proximo-distal type while isolated hyperCKemia was noted in 1.6%. About 60% were born to consanguineous parents and 26.6% had family history of similar illness. Twenty-three patients (18.6%) lost ambulation at follow-up; the median time to loss of independent ambulation was 120 months (range, 72-264). Single-nucleotide variants (SNVs) constituted 78.2% of patients; INDELs 14.5% and 7.3% had both SNVs and INDELs. Earlier age at onset was noted with SNVs. There was no correlation between the other clinical parameters and ambulatory status with the genotype. Thirty-seven (45.7%) novel pathogenic/likely pathogenic (P/LP) variants were identified out of a total of 81 variations. The c.3191G > A variant was the most recurrent mutation. Our cohort constitutes a clinically and genetically heterogeneous group of dysferlinopathies. There is no significant correlation between the clinico-genetic profile and the ambulatory status.
Identifiants
pubmed: 36580222
doi: 10.1007/s10048-022-00707-3
pii: 10.1007/s10048-022-00707-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
43-53Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Bashir R, Britton S, Strachan T, Keers S, Vafiadaki E, Lako M, et al. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet [Internet]. 1998 Sep [cited 2022 Jun 7];20(1):37–42. Available from: https://www.nature.com/articles/ng0998_37
Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet [Internet]. 1998 Sep [cited 2022 Jun 7];20(1):31–6. Available from: https://www.nature.com/articles/ng0998_31
Klinge L, Aboumousa A, Eagle M, Hudson J, Sarkozy A, Vita G, et al. New aspects on patients affected by dysferlin deficient muscular dystrophy. J Neurol Neurosurg Psychiatry [Internet]. 2010 Sep [cited 2022 Jun 9];81(9):946–53. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975994/
Bansal D, Miyake K, Vogel SS, Groh S, Chen CC, Williamson R et al (2003) Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423(6936):168–172
doi: 10.1038/nature01573
Jin SQ, Yu M, Zhang W, Lyu H, Yuan Y, Wang ZX. Dysferlin gene mutation spectrum in a large cohort of Chinese patients with dysferlinopathy. Chin Med J (Engl) [Internet]. 2016 Oct 5 [cited 2022 Jun 7];129(19):2287–93. Available from: https://journals.lww.com/00029330-201610050-00004
Cagliani R, Magri F, Toscano A, Merlini L, Fortunato F, Lamperti C, et al. Mutation finding in patients with dysferlin deficiency and role of the dysferlin interacting proteins annexin A1 and A2 in muscular dystrophies. Hum Mutat [Internet]. 2005 Sep [cited 2022 Jun 27];26(3):283–283. Available from: https://onlinelibrary.wiley.com/doi/10.1002/humu.9364
Polavarapu K, Mathur A, Joshi A, Nashi S, Preethish-Kumar V, Bardhan M et al (2021) A founder mutation in the GMPPB gene [c. 1000G> A (p. Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients. Neurogenetics 22(4):271–85
doi: 10.1007/s10048-021-00658-1
Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Wren J, editor. Bioinformatics [Internet]. 2019 Jun 1 [cited 2022 Jun 29];35(11):1978–80. Available from: https://academic.oup.com/bioinformatics/article/35/11/1978/5146783
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–423
doi: 10.1038/gim.2015.30
Chakravorty S, Nallamilli BRR, Khadilkar SV, Singla MB, Bhutada A, Dastur R, et al. Clinical and genomic evaluation of 207 genetic myopathies in the Indian subcontinent. Front Neurol [Internet]. 2020 [cited 2022 Jun 1];11. Available from: https://www.frontiersin.org/article/10.3389/fneur.2020.559327
Jacobs MB, James MK, Lowes LP, Alfano LN, Eagle M, Muni Lofra R, et al. Assessing dysferlinopathy patients over three years with a new motor scale. Ann Neurol [Internet]. 2021 May [cited 2022 Jun 1];89(5):967–78. Available from: https://onlinelibrary.wiley.com/doi/10.1002/ana.26044
Krahn M, Béroud C, Labelle V, Nguyen K, Bernard R, Bassez G, et al. Analysis of the DYSF mutational spectrum in a large cohort of patients: DYSF mutational spectrum in a large cohort. Hum Mutat [Internet]. 2009 Feb [cited 2022 Jun 3];30(2):E345–75. Available from: https://onlinelibrary.wiley.com/doi/10.1002/humu.20910
Nalini A, Gayathri N. Dysferlinopathy: a clinical and histopathological study of 28 patients from India. Neurol India [Internet]. 2008 [cited 2022 Jun 16];56(3):379. Available from: http://www.neurologyindia.com/text.asp?2008/56/3/379/40964
Rosales XQ, Gastier-Foster JM, Lewis S, Vinod M, Thrush DL, Astbury C, et al. Novel diagnostic features of dysferlinopathies. Muscle Nerve [Internet]. 2010 [cited 2022 Jun 16];42(1):14–21. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.21650
Dastur RS, Gaitonde PS, Kachwala M, Nallamilli BRR, Ankala A, Khadilkar SV, et al. Detection of dysferlin gene pathogenic variants in the Indian population in patients predicted to have a dysferlinopathy using a blood-based monocyte assay and clinical algorithm: a model for accurate and cost-effective diagnosis. Ann Indian Acad Neurol [Internet]. 2017 Jul 1 [cited 2022 Jun 28];20(3):302. Available from: https://www.annalsofian.org/article.asp?issn=0972-2327;year=2017;volume=20;issue=3;spage=302;epage=308;aulast=Dastur;type=0
Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider T, et al. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol [Internet]. 2018 Dec [cited 2022 Jun 1];5(12):1574–87. Available from: https://onlinelibrary.wiley.com/doi/ https://doi.org/10.1002/acn3.649
Xi J, Blandin G, Lu J, Luo S, Zhu W, Beroud C, et al. Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy. Neurol India [Internet]. 2014 Nov 1 [cited 2022 Jul 12];62(6):635. Available from: https://www.neurologyindia.com/article.asp?issn=0028-3886;year=2014;volume=62;issue=6;spage=635;epage=639;aulast=Xi;type=0
Guo QF, Ye ZX, Qiu LL, Lin X, Lai JH, Lin MT, et al. Dysferlinopathy in a cohort of Chinese patients: clinical features, mutation spectrum, and imaging findings. Chin Med J (Engl) [Internet]. 2021 Mar 5 [cited 2022 Jun 3];134(5):622–4. Available from: https://journals.lww.com/10.1097/CM9.0000000000001343
Izumi R, Takahashi T, Suzuki N, Niihori T, Ono H, Nakamura N, et al. The genetic profile of dysferlinopathy in a cohort of 209 cases: genotype–phenotype relationship and a hotspot on the inner DysF domain. Hum Mutat [Internet]. 2020 Sep [cited 2022 Jun 16];41(9):1540–54. Available from: https://onlinelibrary.wiley.com/doi/10.1002/humu.24036
Fernández‐Eulate G, Querin G, Moore U, Behin A, Masingue M, Bassez G, et al. Deep phenotyping of an international series of patients with late‐onset dysferlinopathy. Eur J Neurol [Internet]. 2021 Jun [cited 2022 Jun 1];28(6):2092–102. Available from: https://onlinelibrary.wiley.com/doi/10.1111/ene.14821
Park YE, Kim HS, Lee CH, Nam TS, Choi YC, Kim DS. Two common mutations (p.Gln832X and c.663+1G>C) account for about a third of the DYSF mutations in Korean patients with dysferlinopathy. Neuromuscul Disord [Internet]. 2012 Jun [cited 2022 Jun 16];22(6):505–10. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960896612000028
Takahashi T, Aoki M, Tateyama M, Kondo E, Mizuno T, Onodera Y, et al. Dysferlin mutations in Japanese Miyoshi myopathy: relationship to phenotype. Neurology [Internet]. 2003 Jun 10 [cited 2022 Jun 16];60(11):1799–804. Available from: https://www.neurology.org/lookup/doi/10.1212/01.WNL.0000068333.43005.12
Petersen JA, Kuntzer T, Fischer D, von der Hagen M, Huebner A, Kana V, et al. Dysferlinopathy in Switzerland: clinical phenotypes and potential founder effects. BMC Neurol [Internet]. 2015 Dec [cited 2022 Jun 3];15(1):182. Available from: http://bmcneurol.biomedcentral.com/articles/10.1186/s12883-015-0449-3