The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States

Reddy, Hemakumar M.; Cho, Kyung‐Ah; Lek, Monkol; Estrella, Elicia; Valkanas, Elise; Jones, Michael D.; Mitsuhashi, Satomi; Darras, Basil T.; Amato, Anthony A.; Lidov, Hart G.W.; Brownstein, Catherine A.; Margulies, David M.; Yu, Timothy W.; Salih, Mustafa A.; Kunkel, Louis M.; MacArthur, Daniel G.; Kang, Peter B.

doi:10.1038/jhg.2016.116

Cited by 77 publications

(75 citation statements)

References 47 publications

(57 reference statements)

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“…Recent NGS data prove that 20-30% of myopathic patients carry causative mutations in genes typically not associated with the observed phenotype (16,(32)(33)(34). Many studies (32)(33)(34)(35)(36)(37) identified mutations in genes responsible for LOPD and other metabolic myopathies in patients with a wide range of phenotypes (Table 2). At the same time, a well-known homozygous mutation in ANO5, responsible for a wide spectrum of disorders described under the umbrella term "anoctaminopathy" (38,39), was identified in a patient suspected of having glycogen storage disease because of the presence of glycogen containing vacuoles on muscle biopsy (40).…”

Section: Discussionmentioning

confidence: 99%

Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease

Savarese

Torella

Musumeci

et al. 2018

Neuromuscular Disorders

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Mutations in the GAA gene may cause a late onset Pompe disease presenting with proximal weakness without the characteristic muscle pathology, and therefore a test for GAA activity is the first tier analysis in all undiagnosed patients with hyperCKemia and/or limb-girdle muscular weakness. By using MotorPlex, a targeted gene panel for next generation sequencing, we analyzed GAA and other muscle disease-genes in a large cohort of undiagnosed patients with suspected inherited skeletal muscle disorders (n = 504). In this cohort, 275 patients presented with limb-girdle phenotype and/or an isolated hyperCKemia. Mutational analysis identified GAA mutations in ten patients. Further seven affected relatives were identified by segregation studies. All the patients carried the common GAA mutation c.-32-13T >G and a second, previously reported mutation. In the subcohort of 275 patients with proximal muscle weakness and/or hyperCKemia, we identified late-onset Pompe disease in 10 patients. The clinical overlap between Pompe disease and LGMDs or other skeletal muscle disorders suggests that GAA and the genes causing a metabolic myopathy should be analyzed in all the gene panels used for testing neuromuscular patients. However, enzymatic tests are essential for the interpretation and validation of genetic results.

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Section: Discussionmentioning

confidence: 99%

Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease

Savarese

Torella

Musumeci

et al. 2018

Neuromuscular Disorders

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“…NGS had successfully found causative mutations in many of the monogenic diseases. Like other medical fields, the NGS can be used to identify genes involved in LGMDs and such an application will tremendously broaden our knowledge of LGMDs (Kuhn et al, ; Reddy et al, ; Savarese et al, ; Yu et al, ).…”

Section: Ngs and Lgmdsmentioning

confidence: 99%

Prevalence, pathological mechanisms, and genetic basis of limb‐girdle muscular dystrophies: A review

Taghizadeh

Rezaee

Barreto

et al. 2018

Journal Cellular Physiology

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Limb‐girdle muscular dystrophies (LGMDs) are a highly heterogeneous group of neuromuscular disorders that are associated with weakness and wasting of muscles in legs and arms. Signs and symptoms may begin at any age and usually worsen by time. LGMDs are autosomal disorders with different types and their prevalence is not the same in different areas. New technologies such as next‐generation sequencing can accelerate their diagnosis. Several important pathological mechanisms that are involved in the pathology of the LGMD include abnormalities in dystrophin–glycoprotein complex, the sarcomere, glycosylation of dystroglycan, vesicle and molecular trafficking, signal transduction pathways, and nuclear functions. Here, we provide a comprehensive review that integrates LGMD clinical manifestations, prevalence, and some pathological mechanisms involved in LGMDs.

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“…Several studies reported the use of exomes or gene panels in small LGMD cohorts elsewhere. [12][13][14][15][16] We previously showed that for NMDs such as LGMD, comprehensive genepanel testing has a higher clinical yield (46%) than singlegene testing (15%) or has about 18% higher detection rate of causative pathogenic variants than exome sequencing. 17 Previously, multiple targeted disease-specific panel NGS efforts including that of LGMD for molecular diagnostics were performed.…”

Section: Introductionmentioning

confidence: 99%

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

Nallamilli

Chakravorty

Kesari

et al. 2018

Ann Clin Transl Neurol

130

165

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ObjectiveLimb‐girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal‐muscle weakness with >30 genes associated with different subtypes. The clinical‐genetic overlap among subtypes and with other NMDs complicate disease‐subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical‐trial recruitment. Currently seven LGMD clinical trials are active but still no gene‐therapy‐related treatment is available. Till‐date no nation‐wide large‐scale LGMD sequencing program was performed. Our objectives were to understand LGMD genetic basis, different subtypes’ relative prevalence across US and investigate underlying disease mechanisms.MethodsA total of 4656 patients with clinically suspected‐LGMD across US were recruited to conduct next‐generation sequencing (NGS)‐based gene‐panel testing during June‐2015 to June‐2017 in CLIA‐CAP‐certified Emory‐Genetics‐Laboratory. Thirty‐five LGMD‐subtypes‐associated or LGMD‐like other NMD‐associated genes were investigated. Main outcomes were diagnostic yield, gene‐variant spectrum, and LGMD subtypes’ prevalence in a large US LGMD‐suspected population.ResultsMolecular diagnosis was established in 27% (1259 cases; 95% CI, 26–29%) of the patients with major contributing genes to LGMD phenotypes being: CAPN3(17%), DYSF(16%), FKRP(9%) and ANO5(7%). We observed an increased prevalence of genetically confirmed late‐onset Pompe disease, DNAJB6‐associated LGMD subtype1E and CAPN3‐associated autosomal‐dominant LGMDs. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality.InterpretationOverall, this study has improved our understanding of the relative prevalence of different LGMD subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.

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The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States

Cited by 77 publications

References 47 publications

Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease

Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease

Prevalence, pathological mechanisms, and genetic basis of limb‐girdle muscular dystrophies: A review

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

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