Causative variant profile of collagen VI-related dystrophy in Japan

Abstract Background Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Most reported causative variants are de novo; therefore, to identify possible associated causative variants, comprehensive large cohort studies are required for different ethnicities. Methods We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis. Results Of a total of 130 families with 1–5 members with collagen VI-related dystrophy, 120 had mono-allelic and 10 had bi-allelic variants in COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants. Conclusions We report the causative variant profile of a large set of Japanese cases of collagen VI-related dystrophy. This dataset can be used as a reference to support genetic diagnosis and variant-specific treatment.

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Mutation Profile of Collagen VI-Related Myopathy in Japan

10.21203/rs.3.rs-144076/v1 ◽

2021 ◽

Author(s):

Michio Inoue ◽

Yoshihiko Saito ◽

Takahiro Yonekawa ◽

Megumu Ogawa ◽

Aritoshi Iida ◽

...

Keyword(s):

De Novo ◽

Genetic Diagnosis ◽

Congenital Muscular Dystrophy ◽

Specific Treatment ◽

Japanese Patients ◽

Large Set ◽

Collagen Vi ◽

Allelic Variants ◽

Genetic Analyses ◽

Mutation Profile

Abstract Background: Collagen VI-related myopathy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by mutations in COL6A1, COL6A2, or COL6A3. Most reported mutations are de novo; therefore, to identify possible associated mutations, comprehensive large cohort studies are required for different ethnicities.Methods: We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis.Results: Of a total of 130 families with 1-5 members with collagen VI-related myopathy, 120 had mono-allelic and 10 had bi-allelic variants of COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants. Conclusions: We report the mutation profile of a large set of Japanese cases of collagen VI-related myopathy. This dataset can be used as a reference to support genetic diagnosis and mutation-specific treatment.

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Postmortem Diagnostic Exome Sequencing Identifies a De Novo TUBB3 Alteration in a Newborn With Prenatally Diagnosed Hydrocephalus and Suspected Walker–Warburg Syndrome

Pediatric and Developmental Pathology ◽

10.1177/1093526617698611 ◽

2017 ◽

Vol 21 (3) ◽

pp. 319-323 ◽

Cited By ~ 2

Author(s):

Zöe Powis ◽

Adam C Chamberlin ◽

Christina L Alamillo ◽

Sophia Ceulemans ◽

Lynne M Bird ◽

...

Keyword(s):

Creatine Kinase ◽

Exome Sequencing ◽

De Novo ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Congenital Muscular Dystrophy ◽

Testing Methods ◽

Genetic Etiology ◽

Molecular Genetic Diagnosis ◽

Abnormal Brain

Objective Herein, we report a case of a deceased newborn with prenatally detected hydrocephalus. Postnatal findings included abnormal brain imaging and electroencephalogram, optic nerve abnormalities, and elevated creatine kinase (CK). No underlying genetic etiology had been previously identified for the proband, despite testing with a congenital muscular dystrophy gene panel. Methods Diagnostic exome sequencing (DES) was performed on the proband-parents trio, and candidate alterations were confirmed using automated fluorescence dideoxy sequencing. Results Exome sequencing of the proband, mother and father identified a previously unreported apparently de novo heterozygous tubulin, beta-3 ( TUBB3) c.523G>C (p.V175L) alteration in the proband. Conclusion Overall, DES established a likely molecular genetic diagnosis for a postmortem case after traditional testing methods were uninformative. The DES results allowed for reproductive options, such as preimplantation genetic diagnosis and/or prenatal diagnosis, to be available to the parents in future pregnancies.

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Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

10.1101/074153 ◽

2016 ◽

Cited By ~ 14

Author(s):

Beryl B Cummings ◽

Jamie L Marshall ◽

Taru Tukiainen ◽

Monkol Lek ◽

Sandra Donkervoort ◽

...

Keyword(s):

Genetic Analysis ◽

Transcriptome Sequencing ◽

De Novo ◽

Genetic Diagnosis ◽

Integrated Approach ◽

Disease Diagnosis ◽

Mendelian Disease ◽

Rna Seq ◽

Collagen Vi ◽

Current Standard

AbstractExome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25-50%. Here, we explore the utility of transcriptome sequencing (RNA-seq) as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to over 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrentde novointronic mutation inCOL6A1that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.One Sentence SummaryTranscriptome sequencing improves the diagnostic rate for Mendelian disease in patients for whom genetic analysis has not returned a diagnosis.

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Laminopathies’ Treatments Systematic Review: A Contribution Towards a ‘Treatabolome’

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200596 ◽

2021 ◽

pp. 1-21

Author(s):

Antonio Atalaia ◽

Rabah Ben Yaou ◽

Karim Wahbi ◽

Annachiara De Sandre-Giovannoli ◽

Corinne Vigouroux ◽

...

Keyword(s):

Rare Diseases ◽

Case Reports ◽

Phenotypic Expression ◽

Genetic Diagnosis ◽

Specific Treatment ◽

Case Series ◽

Treatment Recommendations ◽

Scientific Data ◽

Bibliographic Databases ◽

Central Registry

Background: Variants in the LMNA gene, encoding lamins A/C, are responsible for a growing number of diseases, all of which complying with the definition of rare diseases. LMNA-related disorders have a varied phenotypic expression with more than 15 syndromes described, belonging to five phenotypic groups: Muscular Dystrophies, Neuropathies, Cardiomyopathies, Lipodystrophies and Progeroid Syndromes. Overlapping phenotypes are also reported. Linking gene and variants with phenotypic expression, disease mechanisms, and corresponding treatments is particularly challenging in laminopathies. Treatment recommendations are limited, and very few are variant-based. Objective: The Treatabolome initiative aims to provide a shareable dataset of existing variant-specific treatment for rare diseases within the Solve-RD EU project. As part of this project, we gathered evidence of specific treatments for laminopathies via a systematic literature review adopting the FAIR (Findable, Accessible, Interoperable, and Reusable) guidelines for scientific data production. Methods: Treatments for LMNA-related conditions were systematically collected from MEDLINE and Embase bibliographic databases and clinical trial registries (Cochrane Central Registry of Controlled Trials, clinicaltrial.gov and EudraCT). Two investigators extracted and analyzed the literature data independently. The included papers were assessed using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. Results: From the 4783 selected articles by a systematic approach, we identified 78 papers for our final analysis that corresponded to the profile of data defined in the inclusion and exclusion criteria. These papers include 2 guidelines/consensus papers, 4 meta-analyses, 14 single-arm trials, 15 case series, 13 cohort studies, 21 case reports, 8 expert reviews and 1 expert opinion. The treatments were summarized electronically according to significant phenome-genome associations. The specificity of treatments according to the different laminopathic phenotypical presentations is variable. Conclusions: We have extracted Treatabolome-worthy treatment recommendations for patients with different forms of laminopathies based on significant phenome-genome parings. This dataset will be available on the Treatabolome website and, through interoperability, on genetic diagnosis and treatment support tools like the RD-Connect’s Genome Phenome Analysis Platform.

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Clinical impact of post-mortem genetic testing in cardiac death and cardiomyopathy

Open Medicine ◽

10.1515/med-2020-0150 ◽

2020 ◽

Vol 15 (1) ◽

pp. 435-446

Author(s):

Isabelle Marey ◽

Véronique Fressart ◽

Caroline Rambaud ◽

Paul Fornes ◽

Laurent Martin ◽

...

Keyword(s):

Genetic Testing ◽

Cardiac Death ◽

De Novo ◽

Family Care ◽

Prenatal Testing ◽

Added Value ◽

Molecular Testing ◽

Post Mortem ◽

Genetic Analyses ◽

Conventional Autopsy

AbstractPost-mortem genetic analyses may help to elucidate the cause of cardiac death. The added value is however unclear when a cardiac disease is already suspected or affirmed. Our aim was to study the feasibility and medical impact of post-mortem genetic analyses in suspected cardiomyopathy. We studied 35 patients with cardiac death and suspected cardiomyopathy based on autopsy or clinical data. After targeted sequencing, we identified 15 causal variants in 15 patients (yield 43%) in sarcomeric (n = 8), desmosomal (n = 3), lamin A/C (n = 3) and transthyretin (n = 1) genes. The results had various impacts on families, i.e. allowed predictive genetic testing in relatives (15 families), planned early therapeutics based on the specific underlying gene (5 families), rectified the suspected cardiomyopathy subtype (2 families), assessed the genetic origin of cardiomyopathy that usually has an acquired cause (1 family), assessed the diagnosis in a patient with uncertain borderline cardiomyopathy (1 family), reassured the siblings because of a de novo mutation (2 families) and allowed prenatal testing (1 family). Our findings suggest that post-mortem molecular testing should be included in the strategy of family care after cardiac death and suspected cardiomyopathy, since genetic findings provide additional information useful for relatives, which are beyond conventional autopsy.

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Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0433 ◽

2020 ◽

Vol 33 (6) ◽

pp. 691-701 ◽

Cited By ~ 1

Author(s):

Tatsushi Tanaka ◽

Kohei Aoyama ◽

Atsushi Suzuki ◽

Shinji Saitoh ◽

Haruo Mizuno

Keyword(s):

Congenital Hypothyroidism ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Japanese Patients ◽

Thyroid Stimulating Hormone ◽

Allelic Variant ◽

Genetic Investigation ◽

Pathogenic Variants ◽

Recessive Genes ◽

Molecular Genetic Diagnosis

AbstractObjectivesCongenital hypothyroidism (CH) is the most common congenital endocrine disorder. Recent advances in genetic testing have revealed its causative mutations in some CH patients. However, the underlying etiology remains unknown in most patients. This study aimed to perform clinical and genetic investigation in Japanese CH patients to uncover genotype-phenotype correlations.MethodsWe enrolled 136 Japanese patients with transient or permanent CH between April 2015 and March 2017, and performed next-generation sequencing of 19 genes implicated in CH.ResultsWe identified potentially pathogenic bi-allelic variants in DUOX2, TSHR, and TPO in 19, 5, and 1 patient, respectively (autosomal recessive), and a potentially pathogenic mono-allelic variant in NKX2-1 (autosomal dominant) in 1 patient. Molecular genetic diagnosis was highly suggested in 26 patients (19%) from 23 families. We also detected a potentially pathogenic mono-allelic variant in five recessive genes (DUOX2, TSHR, TG, DUOXA2, and TPO) in 31 unrelated patients (23%), although the pathogenicity of these variants remains inconclusive. Patients with bi-allelic DUOX2 variants showed a more severe clinical presentation in infancy than those with bi-allelic TSHR variants. However, this trend reversed beyond infancy. There were no statistical differences in initial thyroid stimulating hormone, free thyroxine, thyroglobulin, and levothyroxine dose as of March 2017 between patients with bi-allelic and mono-allelic DUOX2 variants.ConclusionsThe prevalence of potentially-pathogenic variants in Japanese CH patients was similar to that found by previous reports. Our study demonstrates a genotype-phenotype correlation in Japanese CH patients.

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Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

European Journal of Human Genetics ◽

10.1038/s41431-020-00720-w ◽

2020 ◽

Vol 28 (12) ◽

pp. 1763-1768

Author(s):

Thomas Bourinaris ◽

◽

Damian Smedley ◽

Valentina Cipriani ◽

Isabella Sheikh ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

De Novo ◽

Age At Onset ◽

Genetic Diagnosis ◽

Spastic Paraplegia ◽

Sequencing Data ◽

Juvenile Form ◽

Pathogenic Variants ◽

Degenerative Disorders ◽

Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

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Muscle Protein Alterations in LGMD2I Patients With Different Mutations in the Fukutin-related Protein Gene

Journal of Histochemistry & Cytochemistry ◽

10.1369/jhc.2008.951772 ◽

2008 ◽

Vol 56 (11) ◽

pp. 995-1001 ◽

Cited By ~ 11

Author(s):

Lydia U. Yamamoto ◽

Fernando J. Velloso ◽

Bruno L. Lima ◽

Luciana L.Q. Fogaça ◽

Flávia de Paula ◽

...

Keyword(s):

Muscle Protein ◽

Congenital Muscular Dystrophy ◽

Clinical Severity ◽

Variable Degree ◽

Related Protein ◽

Collagen Vi ◽

Rimmed Vacuoles ◽

Calpain 3 ◽

Protein Alterations ◽

Muscle Biopsies

Fukutin-related protein (FKRP) is a protein involved in the glycosylation of cell surface molecules. Pathogenic mutations in the FKRP gene cause both the more severe congenital muscular dystrophy Type 1C and the milder Limb-Girdle Type 2I form (LGMD2I). Here we report muscle histological alterations and the analysis of 11 muscle proteins: dystrophin, four sarcoglycans, calpain 3, dysferlin, telethonin, collagen VI, α-DG, and α2-laminin, in muscle biopsies from 13 unrelated LGMD2I patients with 10 different FKRP mutations. In all, a typical dystrophic pattern was observed. In eight patients, a high frequency of rimmed vacuoles was also found. A variable degree of α2-laminin deficiency was detected in 12 patients through immunofluorescence analysis, and 10 patients presented α-DG deficiency on sarcolemmal membranes. Additionally, through Western blot analysis, deficiency of calpain 3 and dystrophin bands was found in four and two patients, respectively. All the remaining proteins showed a similar pattern to normal controls. These results suggest that, in our population of LGMD2I patients, different mutations in the FKRP gene are associated with several secondary muscle protein reductions, and the deficiencies of α2-laminin and α-DG on sections are prevalent, independently of mutation type or clinical severity.

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