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

González-Quereda, L.; Rodrí­guez, Marí­a José; Díaz‐Manera, Jordi; Alonso‐Pérez, Jorge; Gallardo, Eduard; Nascimento, A.; Ortez, C.; Benito, Daniel Natera-de; Olivé, Montse; González-Mera, Laura; Munáin, Adolfo López de; Zulaica, Miren; Poza, Juan José; Jericó, Ivonne; Torné, Laura; Riera, Pau; Milisenda, José C.; Sánchez, Aurora; Garrabou, Glòria; Llano, Isabel; Madruga‐Garrido, Marcos; Gallano, P.

doi:10.3390/genes11050539

Cited by 31 publications

(40 citation statements)

References 34 publications

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“…Additionally, with the reporting of new cases, the reported clinical manifestations of mutations in a given gene are likely to expand. Recent large sequencing studies show that the genetic background of muscle diseases is more complex than previously appreciated [ 27 , 28 , 29 ]. In addition, our data suggest that mutations in more than one gene in a patient can result in a more severe phenotype.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Mutations and Putative Phenotype-Affecting Variants in Polish Myofibrillar Myopathy Patients

Potulska‐Chromik

Jędrzejowska

Goś³

et al. 2021

JCM

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Myofibrillar myopathies (MFM) are heterogeneous hereditary muscle diseases with characteristic myopathological features of Z-disk dissolution and aggregates of its degradation products. The onset and progression of the disease are variable, with an elusive genetic background, and around half of the cases lacking molecular diagnosis. Here, we attempted to establish possible genetic foundations of MFM by performing whole exome sequencing (WES) in eleven unrelated families of 13 patients clinically diagnosed as MFM spectrum. A filtering strategy aimed at identification of variants related to the disease was used and included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of muscle-expressed genes, and analysis of the disease-associated interactome. Genetic diagnosis was possible in eight out of eleven cases. Putative causative mutations were found in the DES (two cases), CRYAB, TPM3, and SELENON (four cases) genes, the latter typically presenting with a rigid spine syndrome. Moreover, a variety of additional, possibly phenotype-affecting variants were found. These findings indicate a markedly heterogeneous genetic background of MFM and show the usefulness of next generation sequencing in the identification of disease-associated mutations. Finally, we discuss the emerging concept of variant load as the basis of phenotypic heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Pathogenic Mutations and Putative Phenotype-Affecting Variants in Polish Myofibrillar Myopathy Patients

Potulska‐Chromik

Jędrzejowska

Goś³

et al. 2021

JCM

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“…Many groups have reported their genetic diagnostic strategies for NMDs, with diagnostic yields ranging from 20 to 70% [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Diagnostic rates using NGS are often difficult to compare due to differences not only in genetic strategy but also in cohort selection criteria.…”

Section: From the Classical Molecular Approach To The Genome Scenariomentioning

confidence: 99%

The Increasing Impact of Translational Research in the Molecular Diagnostics of Neuromuscular Diseases

Yubero

Benito

Pijuan

et al. 2021

IJMS

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The diagnosis of neuromuscular diseases (NMDs) has been progressively evolving from the grouping of clinical symptoms and signs towards the molecular definition. Optimal clinical, biochemical, electrophysiological, electrophysiological, and histopathological characterization is very helpful to achieve molecular diagnosis, which is essential for establishing prognosis, treatment and genetic counselling. Currently, the genetic approach includes both the gene-targeted analysis in specific clinically recognizable diseases, as well as genomic analysis based on next-generation sequencing, analyzing either the clinical exome/genome or the whole exome or genome. However, as of today, there are still many patients in whom the causative genetic variant cannot be definitely established and variants of uncertain significance are often found. In this review, we address these drawbacks by incorporating two additional biological omics approaches into the molecular diagnostic process of NMDs. First, functional genomics by introducing experimental cell and molecular biology to analyze and validate the variant for its biological effect in an in-house translational diagnostic program, and second, incorporating a multi-omics approach including RNA-seq, metabolomics, and proteomics in the molecular diagnosis of neuromuscular disease. Both translational diagnostics programs and omics are being implemented as part of the diagnostic process in academic centers and referral hospitals and, therefore, an increase in the proportion of neuromuscular patients with a molecular diagnosis is expected. This improvement in the process and diagnostic performance of patients will allow solving aspects of their health problems in a precise way and will allow them and their families to take a step forward in their lives.

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“…Organization of microtubuli and function of the axoneme; mutations cause primary ciliary dyskinesia, SNP cause skeletal malformations of the limbs in mice [16] TTN Titin Encodes protein of striated muscle, mutations cause neuromuscular diseases [17] IBSP Integrin binding sialoprotein Encodes a major structural protein of bone matrix, discussed as a factor in the development of osteoarthritis [18] CISD2 CDGSH iron sulfur domain 2…”

Section: Phtf1mentioning

confidence: 99%

Iron Deficiency Caused by Intestinal Iron Loss—Novel Candidate Genes for Severe Anemia

Huettmann

Stelljes

Sivalingam

et al. 2021

Genes

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The adult human body contains about 4 g of iron. About 1–2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL. Although red blood cell concentrates and intravenous iron have been substituted every month for years, body iron stores remain depleted. Diagnostics have included several esophago-gastro-duodenoscopies, colonoscopies, MRI of the liver, repetitive bone marrow biopsies, psychological analysis, application of radioactive iron to determine intact erythropoiesis, and measurement of iron excretion in urine and feces. Typically, gastrointestinal bleeding is a major cause of iron loss. Surprisingly, intestinal iron excretion in stool in the patient was repetitively increased, without gastrointestinal bleeding. Furthermore, whole exome sequencing was performed in the patient and additional family members to identify potential causative genetic variants that may cause intestinal iron loss. Under different inheritance models, several rare mutations were identified, two of which (in CISD1 and KRI1) are likely to be functionally relevant. Intestinal iron loss in the current form has not yet been described and is, with high probability, the cause of the severe iron deficiency anemia in this patient.

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

Cited by 31 publications

References 34 publications

Pathogenic Mutations and Putative Phenotype-Affecting Variants in Polish Myofibrillar Myopathy Patients

Pathogenic Mutations and Putative Phenotype-Affecting Variants in Polish Myofibrillar Myopathy Patients

The Increasing Impact of Translational Research in the Molecular Diagnostics of Neuromuscular Diseases

Iron Deficiency Caused by Intestinal Iron Loss—Novel Candidate Genes for Severe Anemia

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