Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders

Abstract Background and aims Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients’ management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis. Methods Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008–2017 who underwent a genetic workup were collected. Results Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT. Conclusion A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients’ management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.

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M-line TTN Mutations in Salih Myopathy: Novel Biallelic Mutation and Review of the Literature

10.21203/rs.3.rs-743096/v1 ◽

2021 ◽

Author(s):

Youssef El Kadiri ◽

Ilham Ratbi ◽

Jaber Lyahyai ◽

Abdelaziz Sefiani

Keyword(s):

Next Generation Sequencing ◽

Sanger Sequencing ◽

Neuromuscular Disorders ◽

Genetic Diagnosis ◽

Congenital Myopathy ◽

Next Generation ◽

Congenital Myopathies ◽

Arab Population ◽

Truncating Mutation ◽

Generation Sequencing

Abstract Background: Salih myopathy (SALMY), also known as early-onset myopathy with fatal cardiomyopathy (EOMFC) is a rare, heterogeneous, and severe form of titinopathies with autosomal recessive inherited neuromuscular disorders that affects both skeletal and cardiac muscles. It was previously identified only in the Arab population with unknown incidence. TTN mutations that have been reported in congenital myopathies are associated with a variety of phenotypic spectrum of titinopathies, which are scattered along the 364 exons of the gene. We report a Moroccan family with an affected patient diagnosed with Salih myopathy by next-generation sequencing (NGS) with a literature review of this rare entity.Methods: Genetic investigation by NGS was performed in a consanguineous Moroccan female child aged 29 months with congenital myopathy. Sanger sequencing confirmation was performed on the patient and both of her parents. Clinical and molecular data of the patient were correlated with 14 patients reported in the literature for congenital myopathy associated with a heart defect or development of dilated cardiomyopathy with at least one mutation in the M-band titin protein as inclusion criteria. Results: Bioinformatics analysis of Clinical Exome Sequencing (CES) data identified a novel homozygous truncating mutation c.106541delA p.(Asp35514Valfs*32) in exon 361 of the TTN gene. Sanger sequencing confirmed the mutation at a homozygous state in the proband and that both her parents are heterozygous carriers. Conclusions: Application of next-generation sequencing in rare genetic heterogeneous forms as SALMY provides more evidently an increasing proportion of congenital myopathies than currently recognized and expands the mutation spectrum of the TTN gene for better guiding the genetic diagnosis with adequate genetic counseling to the Moroccan families.

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Target resequencing of neuromuscular disease-related genes using next-generation sequencing for patients with undiagnosed early-onset neuromuscular disorders

Journal of Human Genetics ◽

10.1038/jhg.2016.79 ◽

2016 ◽

Vol 61 (11) ◽

pp. 931-942 ◽

Cited By ~ 10

Author(s):

Yuri Kitamura ◽

Eri Kondo ◽

Mari Urano ◽

Ryoko Aoki ◽

Kayoko Saito

Keyword(s):

Next Generation Sequencing ◽

Early Onset ◽

Neuromuscular Disease ◽

Neuromuscular Disorders ◽

Next Generation ◽

Disease Related Genes ◽

Generation Sequencing

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Mitochondrial disorders in the Arab Middle East population: the impact of next generation sequencing on the genetic diagnosis.

Journal of Biochemical and Clinical Genetics ◽

10.24911/jbcgenetics/183-1548325196 ◽

2019 ◽

pp. 54-64

Author(s):

Ahmad Alahmad ◽

Hebatallah Muhammad ◽

Angela Pyle ◽

Buthaina Albash ◽

Robert McFarland ◽

...

Keyword(s):

Next Generation Sequencing ◽

Middle East ◽

Genetic Diagnosis ◽

Mitochondrial Disorders ◽

Next Generation ◽

The Impact ◽

Generation Sequencing ◽

Arab Middle East

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Oocyte vitrification is a valid strategy to accumulate gametes for Preimplantation Genetic Diagnosis for Aneuploidy using Next Generation Sequencing

10.26226/morressier.573c1513d462b80296c98b52 ◽

2016 ◽

Author(s):

Sandrine Chamayou

Keyword(s):

Next Generation Sequencing ◽

Preimplantation Genetic Diagnosis ◽

Genetic Diagnosis ◽

Next Generation ◽

Oocyte Vitrification ◽

Generation Sequencing

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A New Next-Generation Sequencing-Based Assay for Concurrent Preimplantation Genetic Diagnosis of Charcot-Marie-Tooth Disease Type 1A and Aneuploidy Screening

Journal of Genetics and Genomics ◽

10.1016/j.jgg.2016.01.003 ◽

2016 ◽

Vol 43 (3) ◽

pp. 155-159 ◽

Cited By ~ 5

Author(s):

Baoheng Gui ◽

Pu Yang ◽

Zhongyuan Yao ◽

Yanping Li ◽

Donge Liu ◽

...

Keyword(s):

Next Generation Sequencing ◽

Preimplantation Genetic Diagnosis ◽

Genetic Diagnosis ◽

Disease Type ◽

Next Generation ◽

Aneuploidy Screening ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Generation Sequencing ◽

Tooth Disease

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Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain

Genes ◽

10.3390/genes11050539 ◽

2020 ◽

Vol 11 (5) ◽

pp. 539

Author(s):

Lidia Gonzalez-Quereda ◽

Maria Jose Rodriguez ◽

Jordi Diaz-Manera ◽

Jorge Alonso-Perez ◽

Eduard Gallardo ◽

...

Keyword(s):

Next Generation Sequencing ◽

Neuromuscular Disorders ◽

Neuromuscular Disorder ◽

Gene Panel ◽

Muscular Dystrophies ◽

Next Generation ◽

Congenital Myasthenic Syndromes ◽

Targeted Next Generation Sequencing ◽

Generation Sequencing ◽

Myasthenic Syndromes

The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients’ clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.

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