Elucidation of the Genetic Cause in Dutch Limb Girdle Muscular Dystrophy Families: A 27-Year’s Journey

2020 ◽  
pp. 1-12
Author(s):  
L. Ten Dam ◽  
M. de Visser ◽  
H.B. Ginjaar ◽  
H.A. van Duyvenvoorde ◽  
S. van Koningsbruggen ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Muscular Dystrophy ◽  
Dna Analysis ◽  
Genetic Diagnosis ◽  
Limb Girdle Muscular Dystrophy ◽  
Facioscapulohumeral Dystrophy ◽  
Related Family ◽  
Whole Exome ◽  
Made In

Background: A Dutch cohort of 105 carefully selected limb girdle muscular dystrophy patients from 68 families has been subject to genetic testing over the last 20 years. After subsequent targeted gene analysis around two thirds (45/68) of the families had received a genetic diagnosis in 2013. Objective: To describe the results of further genetic testing in the remaining undiagnosed limb-girdle muscular dystrophy (LGMD) families in this cohort. Methods: In the families of the cohort for whom no genetic diagnosis was established (n = 23) further testing using Sanger sequencing, next generation sequencing with gene panel analysis or whole-exome sequencing was performed. In one case DNA analysis for facioscapulohumeral dystrophy type 1 was carried out. Results: In eight families no additional genetic tests could be performed. In 12 of the remaining 15 families in which additional testing could be performed a genetic diagnosis was established: two LGMDR1 calpain3-related families with CAPN3 mutations, one LGMDR2 dysferlin-related family with DYSF mutations, three sarcoglycanopathy families (LGMDR3-5 α-, β- and γ-sarcoglycan-related) with SGCA/SGCB/SGCG mutations, one LGMDR8 TRIM 32-related family with TRIM32 mutations, two LGMDR19 GMPPB-related families with GMPPB mutations, one family with MICU1-related myopathy, one family with FLNC-related myopathy and one family with facioscapulohumeral dystrophy type 1. At this moment a genetic diagnosis has been made in 57 of the 60 families of which DNA was available (95%). Conclusion: A genetic diagnosis is obtained in 95% of the families of the original Dutch LGMD cohort of which DNA was available.

scholarly journals Case Report: The Genetic Diagnosis of Duchenne Muscular Dystrophy in the Middle East

2021 ◽  
Vol 9 ◽  
Author(s):  
Fouad Alghamdi ◽  
Asmaa Al-Tawari ◽  
Hadil Alrohaif ◽  
Walaa Alshuaibi ◽  
Hicham Mansour ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Management ◽  
Best Practice ◽  
Middle Eastern ◽  
Genetic Diagnosis ◽  
Signs And Symptoms ◽  
Best Practice Guidelines ◽  
Related Quality

The timely and accurate genetic diagnosis of Duchenne muscular dystrophy (DMD) enables prompt initiation of disease management and genetic counseling and optimal patient care. Despite the existence of best practice guidelines for the diagnosis of DMD, implementation of these recommendations in different parts of the world is challenging. Here, we present 4 unique case studies which illustrate the different diagnostic pathways of patients with DMD in Middle Eastern countries and highlight region-specific challenges to achieving timely and accurate genetic diagnosis of DMD. A lack of disease awareness and consequential failure to recognize the signs and symptoms of DMD significantly contributed to the delayed diagnoses of these patients. Additional challenges included limited available funding for genetic testing and a lack of local specialist and genetic testing centers, causing patients and their families to travel vast distances for appointments in some countries. Earlier and more accurate genetic diagnosis of DMD in this region would allow patients to benefit from effective disease management, leading to improvements in health-related quality of life.

Duchenne Muscular Dystrophy and Early Onset Hypertrophic Cardiomyopathy associated with Mutations in Dystrophin and Hypertrophic Cardiomyopathy-Associated Genes

2020 ◽  
Author(s):  
Liam Aspit ◽  
Noga Arwas ◽  
Aviva Levitas ◽  
Hanna Krymko ◽  
Yoram Etzion ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Hypertrophic Cardiomyopathy ◽  
Muscular Dystrophy ◽  
Early Onset ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Dystrophin Gene ◽  
Whole Exome ◽  
Rare Phenotype ◽  
Muscular Damage

AbstractDuchenne muscular dystrophy (DMD) is a progressive muscular damage disorder caused by mutations in dystrophin gene. Cardiomyopathy may first be evident after 10 years of age and increases in incidence with age. We present a boy diagnosed at 18 months with a rare phenotype of DMD in association with early-onset hypertrophic cardiomyopathy (HCM). The cause of DMD is a deletion of exons 51–54 of dystrophin gene. The cause of HCM was verified by whole exome sequencing. Novel missense variations in two genes: MAP2K5 inherited from the mother and ACTN2 inherited from the father, or de novo. The combination of MAP2K5, ACTN2, and dystrophin mutations, could be causing the HCM in our patient. This is the second patient diagnosed, at relatively young age, with DMD and HCM, with novel variations in genes known to cause HCM. This study demonstrates the need for genetic diagnosis to elucidate the underlying pathology of HCM.

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

2019 ◽  
Vol 20 (1) ◽  
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.

MODY in Ukraine: genes, clinical phenotypes and treatment

2017 ◽  
Vol 30 (10) ◽  
Author(s):  
Evgenia Globa ◽  
Nataliya Zelinska ◽  
Lenka Elblova ◽  
Petra Dusatkova ◽  
Ondrej Cinek ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family Members ◽  
Genetic Diagnosis ◽  
Maturity Onset Diabetes ◽  
Genetic Etiology ◽  
Clinical Phenotypes ◽  
Onset Diabetes ◽  
Patients With Diabetes ◽  
Made In

AbstractBackground:Maturity-onset diabetes of the young (MODY) has not been previously studied in Ukraine. We investigated the genetic etiology in a selected cohort of patients with diabetes diagnosed before 18 years of age, and in their family members.Methods:Genetic testing of the most prevalent MODY genes (Results:A genetic diagnosis of MODY was made in 15/39 affected individuals from 12/36 families (33%).Conclusions:Genetic testing identified pathogenic

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

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Hadis Malek ◽  
Khadijeh Shahrokhabadi ◽  
Saeid Ghavami ◽  
Mohsen Taheri ◽  
Ehsan Ghayoor Karimiani
Keyword(s):  
Muscular Dystrophy ◽  
Exome Sequencing ◽  
Genetic Variant ◽  
Molecular Genetic ◽  
Limb Girdle Muscular Dystrophy ◽  
Muscle Disease ◽  
Genetic Changes ◽  
Molecular Genetic Basis ◽  
Whole Exome ◽  
Muscular Disorders

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.

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

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

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

Gene Reports ◽  
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

scholarly journals Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity

2017 ◽  
Vol 177 (6) ◽  
pp. 485-501 ◽  
Author(s):  
Lucy Shapiro ◽  
Sumana Chatterjee ◽  
Dina G Ramadan ◽  
Kate M Davies ◽  
Martin O Savage ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Candidate Gene ◽  
Short Stature ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Genetic Defect ◽  
Significant Proportion ◽  
Genetic Diagnosis ◽  
Whole Exome

Background GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. Objective To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. Methods We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. Results A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver–Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. Conclusions Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres.

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