Role of DYSF Genetic Variant in Limb Girdle Muscular Dystrophy: A Case Report

Introduction: Muscular dystrophy is a hereditary degenerative muscle disease which progressively reduces the strength of the muscles that control movement. In this study, we tried to investigate genetic variants in muscular dystrophy using sequencing of whole exons. Case Presentation: A family with two affected patients with muscular dystrophy was referred for genetic counseling followed by exome sequencing testing on the proband. After filling out informed consent, blood samples were obtained from each available family member. Candidate genetic variant was confirmed using Sanger sequencing. Conclusions: Exome data analysis revealed a variant of c.2864 + 1G > A in the proband, which altered the exon-intron 26 splice site within the DYSF gene. Genetic changes in this gene are known to be associated with muscular disorders, such as limb-girdle muscular dystrophy and other dysferlinopathies. Assessment of this genetic variant in the patient's sister also showed homozygous variant. Since the patient's sister was married to her cousin, the same variant was tested in her husband, which was normal homozygous. NGS-based techniques, including whole-exome sequencing, can identify the molecular genetic basis of the disease in families with limb-girdle muscular dystrophy. The results can be helpful in identifying potential carriers in the family and in prenatal diagnosis to the families involved.

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Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10

BMC Medical Genetics ◽

10.1186/s12881-019-0895-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 5

Author(s):

Amjad Khan ◽

Rongrong Wang ◽

Shirui Han ◽

Muhammad Umair ◽

Safdar Abbas ◽

...

Keyword(s):

Muscular Dystrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Missense Variant ◽

Pathogenic Variant ◽

Limb Girdle Muscular Dystrophy ◽

Molecular Diagnostic ◽

Sequencing Analysis ◽

Whole Exome

Abstract Background Limb-girdle muscular dystrophies (LGMDs) are large group of heterogeneous genetic diseases, having a hallmark feature of muscle weakness. Pathogenic mutations in the gene encoding the giant skeletal muscle protein titin (TTN) are associated with several muscle disorders, including cardiomyopathy, recessive congenital myopathies and limb-girdle muscular dystrophy (LGMD) type10. The phenotypic spectrum of titinopathies is expanding, as next generation sequencing (NGS) technology makes screening of this large gene possible. Aim This study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive LGMD type 10. Methods DNA from peripheral blood samples were obtained, whole exome sequencing (WES) was performed and several molecular and bioinformatics analysis were conducted to identify the pathogenic variant. TTN coding and near coding regions were further amplified using PCR and sequenced via Sanger sequencing. Results Whole exome sequencing analysis revealed a novel homozygous missense variant (c.98807G > A; p.Arg32936His) in the TTN gene in the index patients. No heterozygous individuals in the family presented LGMD features. The variant p.Arg32936His leads to a substitution of the arginine amino acid at position 32,936 into histidine possibly causing LGMD type 10. Conclusion We identified a homozygous missense variant in TTN, which likely explains LGMD type 10 in this family in line with similar previously reported data. Our study concludes that WES is a successful molecular diagnostic tool to identify pathogenic variants in large genes such as TTN in highly inbred population.

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Limb-girdle muscular dystrophy due to a novel homozygous ISPD gene mutation disclosed by whole exome sequencing

Journal of the Neurological Sciences ◽

10.1016/j.jns.2015.08.1205 ◽

2015 ◽

Vol 357 ◽

pp. e339

Author(s):

V. Mastorodemos ◽

E. Vogiatzi ◽

H. Latsoudis ◽

P. Vorgia ◽

G. Amoiridis ◽

...

Keyword(s):

Muscular Dystrophy ◽

Exome Sequencing ◽

Gene Mutation ◽

Whole Exome Sequencing ◽

Limb Girdle Muscular Dystrophy ◽

Whole Exome

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Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients

Human Genomics ◽

10.1186/s40246-018-0167-1 ◽

2018 ◽

Vol 12 (1) ◽

Cited By ~ 13

Author(s):

Jakub Piotr Fichna ◽

Anna Macias ◽

Marcin Piechota ◽

Michał Korostyński ◽

Anna Potulska-Chromik ◽

...

Keyword(s):

Muscular Dystrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Limb Girdle Muscular Dystrophy ◽

Pathogenic Mutations ◽

Whole Exome

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Whole exome sequencing reveals a homozygous SGCB variant in a Pakhtun family with limb girdle muscular dystrophy (LGMDR4) phenotype

Gene Reports ◽

10.1016/j.genrep.2020.101014 ◽

2021 ◽

Vol 22 ◽

pp. 101014

Author(s):

Muhammad Tariq ◽

Muhammad Latif ◽

Memona Inam ◽

Amin Jan ◽

Nousheen Bibi ◽

...

Keyword(s):

Muscular Dystrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Limb Girdle Muscular Dystrophy ◽

Whole Exome

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Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy

JAMA Neurology ◽

10.1001/jamaneurol.2015.2274 ◽

2015 ◽

Vol 72 (12) ◽

pp. 1424 ◽

Cited By ~ 86

Author(s):

Roula Ghaoui ◽

Sandra T. Cooper ◽

Monkol Lek ◽

Kristi Jones ◽

Alastair Corbett ◽

...

Keyword(s):

Muscular Dystrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Limb Girdle Muscular Dystrophy ◽

Whole Exome

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Whole exome sequencing identified a novel DAG1 mutation in a patient with rare, mild and late age of onset muscular dystrophy-dystroglycanopathy

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.13979 ◽

2018 ◽

Vol 23 (2) ◽

pp. 811-818 ◽

Cited By ~ 5

Author(s):

Yi Dai ◽

Shengran Liang ◽

Xue Dong ◽

Yanhuan Zhao ◽

Haitao Ren ◽

...

Keyword(s):

Muscular Dystrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Age Of Onset ◽

Whole Exome

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Corrigendum: Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy

Frontiers in Genetics ◽

10.3389/fgene.2021.684042 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yu Xia ◽

Yijie Feng ◽

Lu Xu ◽

Xiaoyang Chen ◽

Feng Gao ◽

...

Keyword(s):

Case Report ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Spinal Muscular Atrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Muscular Atrophy ◽

Whole Exome

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Determination of genetic changes in etiology of autism spectrum disorder in twins by whole-exome sequencing

Gene Reports ◽

10.1016/j.genrep.2020.100618 ◽

2020 ◽

Vol 19 ◽

pp. 100618

Author(s):

Ceyda Hayretdag ◽

Pinar Algedik ◽

Cumhur Gokhan Ekmekci ◽

Ozlem Bozdagi Gunal ◽

Umut Agyuz ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Genetic Changes ◽

Whole Exome

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Proposal for Modification of Cahan's Criteria Utilizing Molecular Genetic Analyses for Cases without Baseline Histopathology: A Unique Method Applicable to Primary Radiosurgery

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0038-1655759 ◽

2018 ◽

Vol 80 (01) ◽

pp. 010-017

Author(s):

Aaron Rusheen ◽

James Smadbeck ◽

Lisa Schimmenti ◽

Eric Klee ◽

Michael Link ◽

...

Keyword(s):

Next Generation Sequencing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Vestibular Schwannoma ◽

Radiation Treatment ◽

Molecular Genetic ◽

Secondary Malignancy ◽

Whole Exome ◽

Mate Pair ◽

Generation Sequencing

Background Cahan's criteria have been utilized since 1948 to establish causality between prior radiation treatment and the development of secondary malignancy. One major criterion specifies that histological and radiographic evidence collected before and after radiation treatment must confirm separate tumor types; however, pretreatment biopsy is rarely obtained prior to radiosurgery for vestibular schwannoma and many other skull base and cranial lesions. Therefore, in these cases Cahan's criteria cannot be validly applied. Objective This article proposes an update to Cahan's criteria using modern molecular genetic analysis for cases lacking baseline histopathology. Methods Mate-pair sequencing and whole exome sequencing of a cerebellopontine angle undifferentiated high-grade pleomorphic sarcoma (UHGPS) that developed after stereotactic radiosurgery of a presumed benign vestibular schwannoma. Results Mate-pair sequencing and whole exome sequencing of the sarcoma revealed complex chromosomal aberrations. Notably, the tumor contained a deletion in the NF2 gene at 22q12 and an in-frame deletion on exon 5 of the remaining copy of NF2. Biallelic events impacting NF2 are atypical for UHGPS but are characteristic for vestibular schwannoma. These findings help support the conclusion that the UHGPS arose from a benign vestibular schwannoma all along. Conclusions Next-generation sequencing can be successfully applied to a radiation-induced sarcoma when both the original and malignant tumors harbor separate signature genetic markers. As our understanding of the genetic profile of various tumors expand, we believe that next-generation sequencing and other genomic tools will play an increasingly important role in establishing causality between radiation and the development of secondary malignancy.

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