Mridul Johari

Harry Perkins Institute of Medical Research

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Marco Savarese

University of Helsinki

Peter Hackman

Folkhälsans Forskningscentrum

Bjarne Udd

Folkhälsans Forskningscentrum

Per Harald Jonson

Folkhälsans Forskningscentrum

Annalaura Torella

University of Campania "Luigi Vanvitelli"

Bjarne Udd

Tampere University Hospital

Volker Straub

Newcastle upon Tyne Hospitals NHS Foundation Trust

Ana Töpf

Newcastle University

Anna Vihola

University of Helsinki

Gisèle Bonne

Centre de Recherche en Myologie

Cooperative Institutions

Inserm

146

University College London

117

University of Helsinki

Radboud University Nijmegen

Radboud University Medical Center

Sorbonne Université

Assistance Publique – Hôpitaux de Paris

National Hospital for Neurology and Neurosurgery

Genomics England

Istituti di Ricovero e Cura a Carattere Scientifico

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Copy number variation analysis increases the diagnostic yield in muscle diseases

Neurology Genetics (2017)

Salla Välipakka Marco Savarese Mridul Johari Lydia Sagath Meharji Arumilli

Objective:

Copy number variants (CNVs) were analyzed from next-generation sequencing data, with the aim of improving diagnostic yield in skeletal muscle disorder cases.

Methods:

Four publicly available bioinformatic analytic tools were used to analyze CNVs from sequencing data from patients with muscle diseases. The patients were previously analyzed with a targeted gene panel for single nucleotide variants and small insertions and deletions, without achieving final diagnosis. Variants detected by multiple CNV analysis tools were verified with either array comparative genomic hybridization or PCR. The clinical significance of the verified CNVs was interpreted, considering previously identified variants, segregation studies, and clinical information of the patient cases.

Results:

Combining analysis of all different mutation types enabled integration of results and identified the final cause of the disease in 9 myopathy cases. Complex effects like compound heterozygosity of different mutation types and compound disease arising from variants of different genes were unraveled. We identified the first large intragenic deletion of the titin (TTN) gene implicated in the pathogenesis of a severe form of myopathy. Our work also revealed a "double-trouble" effect in a patient carrying a single heterozygous insertion/deletion mutation in the TTN gene and a Becker muscular dystrophy causing deletion in the dystrophin gene.

Conclusions:

Causative CNVs were identified proving that analysis of CNVs is essential for increasing the diagnostic yield in muscle diseases. Complex severe muscular dystrophy phenotypes can be the result of different mutation types but also of the compound effect of 2 different genetic diseases.

Variation (astronomy)

10.1212/nxg.0000000000000204

Cite

Citations (21)

An unusual ryanodine receptor 1 (RYR1) phenotype

Neurology (2019)

Manu Jokela Giorgio Tasca Anna Vihola Eugenio Mercuri Per Harald Jonson

To identify the genetic defect causing a distal calf myopathy with cores.Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family.A novel deletion-insertion mutation in ryanodine receptor 1 (RYR1) was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique RYR1-mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families.Our findings expand the spectrum of RYR1-related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported RYR1 mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.

Central core disease

Malignant hyperthermia

Congenital myopathy

Proband

Sanger sequencing

Compound heterozygosity

10.1212/wnl.0000000000007246

Cite

Citations (20)

Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes

European Journal of Human Genetics (2024)

German Demidov Steven Laurie Annalaura Torella Giulio Piluso Marcello Scala

Abstract Structural variants (SVs), including large deletions, duplications, inversions, translocations, and more complex events have the potential to disrupt gene function resulting in rare disease. Nevertheless, current pipelines and clinical decision support systems for exome sequencing (ES) tend to focus on small alterations such as single nucleotide variants (SNVs) and insertions-deletions shorter than 50 base pairs (indels). Additionally, detection and interpretation of large copy-number variants (CNVs) are frequently performed. However, detection of other types of SVs in ES data is hampered by the difficulty of identifying breakpoints in off-target (intergenic or intronic) regions, which makes robust identification of SVs challenging. In this paper, we demonstrate the utility of SV calling in ES resulting in a diagnostic yield of 0.4% (23 out of 5825 probands) for a large cohort of unsolved patients collected by the Solve-RD consortium. Remarkably, 8 out of 23 pathogenic SV were not found by comprehensive read-depth-based CNV analysis, resulting in a 0.13% increased diagnostic value.

Rare disease

Exome

10.1038/s41431-024-01637-4

Cite

Citations (5)

Loss-of-function variants inJPH1cause congenital myopathy with prominent facial and ocular involvement

Journal of Medical Genetics (2024)

Mridul Johari Ana Töpf Chiara Folland Jennifer Duff Lein Dofash

Weakness of facial, ocular and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca

Loss function

Congenital myopathy

10.1136/jmg-2024-109970

Cite

Citations (0)

Current advance on distal myopathy genetics

Current Opinion in Neurology (2024)

Johanna Ranta‐aho Mridul Johari B. Udd

Purpose of review Distal myopathies are a clinically heterogenous group of rare, genetic muscle diseases, that present with weakness in hands and/or feet at onset. Some of these diseases remain accentuated in the distal muscles whereas others may later progress to the proximal muscles. In this review, the latest findings related to genetic and clinical features of distal myopathies are summarized. Recent findings Variants in SMPX , DNAJB2, and HSPB6 have been identified as a novel cause of late-onset distal myopathy and neuromyopathy. In oculopharyngodistal myopathies, repeat expansions were identified in two novel disease-causing genes, RILPL1 and ABCD3. In multisystem proteinopathies, variants in HNRNPA1 and TARDBP , genes previously associated with amyotrophic lateral sclerosis, have been shown to cause late-onset distal myopathy without ALS. In ACTN2 -related distal myopathy, the first recessive forms of the disease have been described, adding it to the growing list of genes were both dominant and recessive forms of myopathy are present. Summary The identification of novel distal myopathy genes and pathogenic variants contribute to our ability to provide a final molecular diagnosis to a larger number of patients and increase our overall understanding of distal myopathy genetics and pathology.

10.1097/wco.0000000000001299

Cite

Citations (0)

VP178 Multiomics needed to increase the detection rate of myopathy patients

Neuromuscular Disorders (2023)

Ruth Owusu Mridul Johari Sara Lehtinen Manu Jokela Johanna Palmio

Mendelian inheritance

Exome

10.1016/j.nmd.2023.07.178

Cite

Citations (0)

Identification and Characterization of Splicing Defects by Single-Molecule Real-Time Sequencing Technology (PacBio)

Journal of Neuromuscular Diseases (2020)

Marco Savarese Talha Qureshi Annalaura Torella Pia Laine Teresa Giugliano

Although DNA-sequencing is the most effective procedure to achieve a molecular diagnosis in genetic diseases, complementary RNA analyses are often required. Reverse-Transcription polymerase chain reaction (RT-PCR) is still a valuable option when the clinical phenotype and/or available DNA-test results address the diagnosis toward a gene of interest or when the splicing effect of a single variant needs to be assessed. We use Single-Molecule Real-Time sequencing to detect and characterize splicing defects and single nucleotide variants in well-known disease genes (DMD, NF1, TTN). After proper optimization, the procedure could be used in the diagnostic setting, simplifying the workflow of cDNA analysis.

10.3233/jnd-200523

Cite

Citations (9)

Neuromuscular Disorders (2022)

Mridul Johari G. Papadimas C. Papadopoulos S. Xirou M. Savarese

10.1016/j.nmd.2022.07.271

Cite

Citations (0)

Heterozygous loss-of-function variants in SPTAN1 cause a novel early childhood onset distal myopathy with chronic neurogenic features

medRxiv (Cold Spring Harbor Laboratory) (2024)

Jonathan De Winter Liedewei Van de Vondel Biljana Ermanoska Alice Monticelli Arnaud Isapof

ABSTRACT Background Neurogenetic disorders caused by pathogenic variants in four genes encoding non-erythrocytic spectrins ( SPTAN1, SPTBN1, SPTBN2, SPTBN4) range from peripheral and central nervous system involvement to complex syndromic presentations. Heterozygous pathogenic variants in SPTAN1 are exemplary for this diversity with phenotypes spanning almost the entire spectrum. Methods Through international collaboration we identified 14 families with genetically unsolved distal weakness and unreported heterozygous SPTAN1 loss-of-function variants including frameshift, nonsense and splice-acceptor variants. Clinical data, electrophysiology, muscle CT or MRI and muscle biopsy findings were collected and standardized. SPTAN1 protein, mRNA expression analysis and cDNA sequencing was performed on muscle tissue from two patients. Results All 20 patients presented with early childhood onset distal weakness. The severity varied both within families and between different families. Foot abnormalities ranged from hammer toes and pes cavus to distal arthrogryposis. Electrophysiology showed mixed myogenic and neurogenic features. Muscle MRI or CT in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes with mild dystrophic and chronic neurogenic changes in 7 patients. Finally, we provide proof for nonsense mediated decay in tissues derived from two patients. Conclusions We provide evidence for the association of SPTAN1 loss-of-function variants with childhood onset distal myopathy in 14 families. This finding extends the phenotypic spectrum of SPTAN1 loss-of-function variants ranging from intellectual disability to distal weakness with a predominant myogenic cause. KEY MESSAGES ⋄ SPTAN1 loss-of-function variants, including frameshift, nonsense and splice site variants cause a novel childhood onset distal weakness syndrome with primarily skeletal muscle involvement. ⋄ Hereditary motor neuropathies and distal myopathic disorders present a well-known diagnostic challenge as they demonstrate substantial clinical and genetic overlap. The emergence of SPTAN1 loss-of-function variants serves as a noteworthy example, highlighting a growing convergence in the spectrum of genotypes linked to both hereditary motor neuropathies and distal myopathies.

Loss function

10.1101/2024.09.23.24313872

Cite

Citations (1)

Correction to: Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases

European Journal of Human Genetics (2021)

Birte Zurek Kornelia Ellwanger Lisenka E.L.M. Vissers Rebecca Schüle Matthis Synofzik

Data Sharing

10.1038/s41431-021-00936-4

Cite

Citations (1)