Limb girdle muscular dystrophy due to mutations in <i>POMT2</i>

Østergaard, S.; Johnson, Katherine; Stojkovic, Tanya; Krag, Thomas; Ridder, Willem De; Jonghe, Peter De; Baets, Jonathan; Claeys, Kristl G.; Fernández‐Torrón, Roberto; Phillips, Lauren; Töpf, Ana; Colomer, J.; Nafissi, Shahriar; Jamal-Omidi, Shirin; Bouchet-Seraphin, C.; Leturcq, F.; MacArthur, Daniel G.; Lek, Monkol; Xu, Liwen; Nelson, Isabelle; Straub, Volker; Vissing, John

doi:10.1136/jnnp-2017-317018

Cited by 25 publications

(32 citation statements)

References 29 publications

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“…The participating centers provided consent for data sharing facilitated by the European Genome-Phenome Archive (EGA) and RD-Connect (https://platform.rd-connect.eu/), and we advocate that adopting such an approach will enable future matchmaking between extremely rare cases, such as BVESrelated myopathy 34 or LGMD R21 POGLUT1-related. 35 In addition, thanks to the large cohort size and standardized deep phenotypic data, we were able to expand the clinical and mutational spectrum of known causative genes, such as TRIM32, 36 POMK, 37 DPM3, 38 POMT2, 39 and other dystroglycanopathies. 40 Based on our findings from this large-scale international collaboration, we suggest a new diagnostic approach in the clinic and/or private health providers.…”

Section: Discussionmentioning

confidence: 99%

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Töpf

Johnson

Bates

et al. 2020

Genetics in Medicine

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Purpose: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Methods: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. Results: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining wellcharacterized unsolved patients (48%) need further investigation. Conclusion: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

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Section: Discussionmentioning

confidence: 99%

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Töpf

Johnson

Bates

et al. 2020

Genetics in Medicine

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“…According to previous literature, patients with LGMD2N exhibit a wide variety of clinical severity. Muscle magnetic resonance imaging (MRI) with cognitive function testing was proposed to differentiate LGMD2N from LGMD2A [34]. A similar approach could be used to differentiate between LGMD2N and other types of alpha-dystroglycanopathy with LGMD phenotype as some differences were noted between LGMD2I and 2N in our cohort.…”

Section: Discussionmentioning

confidence: 94%

Clinical, pathological, imaging, and genetic characterization in a Taiwanese cohort with limb-girdle muscular dystrophy

Liang

Jong

Wang

et al. 2020

Orphanet J Rare Dis

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Background: Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous, hereditary disease characterized by limb-girdle weakness and histologically dystrophic changes. The prevalence of each subtype of LGMD varies among different ethnic populations. This study for the first time analyzed the phenotypes and genotypes in Taiwanese patients with LGMD in a referral center for neuromuscular diseases (NMDs). Results: We enrolled 102 patients clinically suspected of having LGMD who underwent muscle biopsy with subsequent genetic analysis in the previous 10 years. On the basis of different pathological categories, we performed sequencing of target genes or panel for NMDs and then identified patients with type 1B, 1E, 2A, 2B, 2D, 2I, 2G, 2 N, and 2Q. The 1B patients with LMNA mutation presented with mild limb-girdle weakness but no conduction defect at the time. All 1E patients with DES mutation exhibited predominantly proximal weakness along with distal weakness. In our cohort, 2B and 2I were the most frequent forms of LGMD; several common or founder mutations were identified, including c.1097_1099delACA (p.Asn366del) in DES, homozygous c.101G > T (p.Arg34Leu) in SGCA, homozygous c.26_33dup (p.Glu12Argfs*20) in TCAP, c.545A > G (p.Tyr182Cys), and c.948delC (p.Cys317Alafs*111) in FKRP. Clinically, the prevalence of dilated cardiomyopathy in our patients with LGMD2I aged > 18 years was 100%, much higher than that in European cohorts. The only patient with LGMD2Q with PLEC mutation did not exhibit skin lesions or gastrointestinal abnormalities but had mild facial weakness. Muscle imaging of LGMD1E and 2G revealed a more uniform involvement than did other LGMD types. Conclusion: Our study revealed that detailed clinical manifestation together with muscle pathology and imaging remain critical in guiding further molecular analyses and are crucial for establishing genotype-phenotype correlations. We also determined the common mutations and prevalence for different subtypes of LGMD in our cohort, which could be useful when providing specific care and personalized therapy to patients with LGMD.

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“…The condition is characterized by destruction of muscle and its replacement by fatty and fibrous tissue [ 52 ]. Mutations in POMT2 cause severe congenital muscular dystrophy and are associated with a milder limb-girdle muscular dystrophy phenotype [ 53 ]. Fukutin-related protein ( FKRP ) was identified based on its sequence homology with fukutin [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

Network-based association analysis to infer new disease-gene relationships using large-scale protein interactions

Suratanee

Plaimas

2018

PLoS ONE

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Protein-protein interactions integrated with disease-gene associations represent important information for revealing protein functions under disease conditions to improve the prevention, diagnosis, and treatment of complex diseases. Although several studies have attempted to identify disease-gene associations, the number of possible disease-gene associations is very small. High-throughput technologies have been established experimentally to identify the association between genes and diseases. However, these techniques are still quite expensive, time consuming, and even difficult to perform. Thus, based on currently available data and knowledge, computational methods have served as alternatives to provide more possible associations to increase our understanding of disease mechanisms. Here, a new network-based algorithm, namely, Disease-Gene Association (DGA), was developed to calculate the association score of a query gene to a new possible set of diseases. First, a large-scale protein interaction network was constructed, and the relationship between two interacting proteins was calculated with regard to the disease relationship. Novel plausible disease-gene pairs were identified and statistically scored by our algorithm using neighboring protein information. The results yielded high performance for disease-gene prediction, with an F-measure of 0.78 and an AUC of 0.86. To identify promising candidates of disease-gene associations, the association coverage of genes and diseases were calculated and used with the association score to perform gene and disease selection. Based on gene selection, we identified promising pairs that exhibited evidence related to several important diseases, e.g., inflammation, lipid metabolism, inborn errors, xanthomatosis, cerebellar ataxia, cognitive deterioration, malignant neoplasms of the skin and malignant tumors of the cervix. Focusing on disease selection, we identified target genes that were important to blistering skin diseases and muscular dystrophy. In summary, our developed algorithm is simple, efficiently identifies disease–gene associations in the protein-protein interaction network and provides additional knowledge regarding disease-gene associations. This method can be generalized to other association studies to further advance biomedical science.

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Limb girdle muscular dystrophy due to mutations in POMT2

Abstract: NCT02759302.

Cited by 25 publications

References 29 publications

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Clinical, pathological, imaging, and genetic characterization in a Taiwanese cohort with limb-girdle muscular dystrophy

Network-based association analysis to infer new disease-gene relationships using large-scale protein interactions

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