Next-Generation Sequencing to Diagnose Muscular Dystrophy, Rhabdomyolysis, and HyperCKemia

Wu, Liang; Brady, Lauren; Shoffner, John M.; Tarnopolsky, Mark A.

doi:10.1017/cjn.2017.286

Cited by 33 publications

(31 citation statements)

References 81 publications

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“…The only variants of potential pathogenicity and significance were two novel heterozygous variants in exon 2 of the PGAM2 gene (c.426C > A, p.Tyr142Ter; c.533delG, p.Gly178Alafs*31). This patient's genetic results were previously reported (Patient M53 [ 22 ]). Phosphoglycerate mutase enzyme activity was 21% of normal activity (49.9 μmol/min/g tissue [reference mean = 236.2 +/− 51.9 μmol/min/g tissue]), Robert Guthrie Biochemical & Molecular Genetics Laboratory, Kaleida Health System, Buffalo, NY).…”

Section: Case Reportsupporting

confidence: 64%

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Novel heterozygous mutations in the PGAM2 gene with negative exercise testing

Sidhu

Brady

Vladutiu

et al. 2018

Molecular Genetics and Metabolism Reports

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Pathogenic variants in the PGAM2 gene are associated with glycogen storage disease type X (GSDX) and is characterized by exercise induced muscle cramping, weakness, myoglobinuria, and often tubular aggregates in skeletal muscle. We report here a patient diagnosed with GSDX at 52 years of age with a normal increase in post-exercise lactate with both anaerobic and aerobic exercise. Genetic testing found two novel PGAM2 variants (c.426C > A, p.Tyr142Ter and c.533delG, p.Gly178Alafs*31).

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Section: Case Reportsupporting

confidence: 64%

“…PGAM2 and other enzymes in glycolysis) and pseudo-metabolic genes (i.e., dystrophinopathies, sarcoglycanopathies, malignant hyperthermia, etc.) [ 22 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Novel heterozygous mutations in the PGAM2 gene with negative exercise testing

Sidhu

Brady

Vladutiu

et al. 2018

Molecular Genetics and Metabolism Reports

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“…Our use of massive parallel sequencing with a multigene panel combined with the application of stringent bioinformatics filters, and integration of muscle phenotypes (both clinical and morphological), produced a 50% diagnostic yield, a rate higher than those previously reported. 39,40 This difference is likely related to the combination of genotype with integrated clinico-morphological phenotype data in the present study, to its more homogeneous population (mostly adults in our cohort as opposed to the mixed populations studied by others), to technical improvements implicit in more recent gene panel technologies, or to a combination of these factors. There were no straightforward differences between the solved and unsolved participants, with clinical features and serum CK values being roughly the same in the 2 subgroups.…”

Section: Discussionmentioning

confidence: 80%

“…Some studies have also addressed, among other aspects, the genotype of patients with isolated hyperCKemia, reporting a limited diagnostic yield (21%) in fewer than 40 patients. 39,40…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing approach to hyperCKemia

et al. 2019

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ObjectiveNext-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition.MethodsSixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies.ResultsA molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%. Variants of unknown significance were found in 17 patients (26%), whereas 16 cases (24%) remained molecularly undefined. The major features of the diagnosed cases were mild proximal muscle weakness (found in 27%) and myalgia (in 24%). Fourteen patients with a molecular diagnosis and mild myopathic features on muscle biopsy remained asymptomatic at a 24-month follow-up.ConclusionsThis study of patients with undiagnosed hyperCKemia, highlighting the advantages of NGS used as a first-tier diagnostic approach in genetically heterogeneous conditions, illustrates the ongoing evolution of molecular diagnosis in the field of clinical neurology. Isolated hyperCKemia can be the sole feature alerting to a progressive muscular disorder requiring careful surveillance.

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“…Use of such markers has since been replaced by other techniques such as Sanger sequencing which can detect both patients and at‐risk family members carrying small sequence mutations. Additionally, next generation sequencing‐based tests can detect both deletion or duplication mutations in addition to the small sequence mutations (Evilä, Arumilli, Udd, & Hackman, ; Gonorazky et al, ; Hegde et al, ; Okubo et al, ; Roberts, Barby, Manners, Bobrow, & Bentley, ; Wang et al, ; Wei et al, ; Wu, Brady, Shoffner, & Tarnopolsky, ).…”

Section: Introductionmentioning

confidence: 99%

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy

Tomar

Moorthy

Sethi

et al. 2019

American J of Med Genetics Pt C

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Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive disorders caused by mutations in the DMD gene. Emerging therapies targeting patients with specific mutations are now becoming a reality for many of these patients. Precise molecular diagnosis is essential to facilitate the identification of possible new treatments for patients in the local context. In this study, we screened 145 dystrophinopathic patients in Singapore and assessed their molecular status for eligibility to current emerging genetic therapies. Overall, 140 (96.5%) of all patients harbored pathogenic DMD mutations comprising 95 exonic deletions (65.5%), 14 exonic duplications (9.7%), and 31 pathogenic small mutations (21.4%). Nonsense and frameshift mutations constitute 83.9% of all the small mutations. We found 71% (103/145) of all Singaporean dystrophinopathy patients to be theoretically amenable for exon skipping, either through skipping of single (53.1%) or multiple exons (17.9%).This approach is applicable to 81.1% (77/95) of patients carrying deletions and 83.9% (26/31) of those with small mutations. Eteplirsen induced skipping of exon 51 is applicable to 12.4% of local patients. Nonsense read-through therapy was found to be applicable in another 12.4% of all patients. Mutation screening is crucial for providing insights into the underlying genetic signature of the disease in the local population and contributes toward existing information on DMD mutations in Asia and globally. This will guide future targeted drug development and clinical trial planning for this disease. K E Y W O R D SBecker muscular dystrophy, Duchenne muscular dystrophy, dystrophinopathy, genetic diagnosis, mutation spectrum

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Next-Generation Sequencing to Diagnose Muscular Dystrophy, Rhabdomyolysis, and HyperCKemia

Cited by 33 publications

References 81 publications

Novel heterozygous mutations in the PGAM2 gene with negative exercise testing

Novel heterozygous mutations in the PGAM2 gene with negative exercise testing

Next-generation sequencing approach to hyperCKemia

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy

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