Exploring the utility of whole‐exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness

Hanchard, NA; Murdock,; Magoulas, P.L.; Bainbridge, Matthew N.; Muzny, Donna M.; Wu, Yueqin; Wang, M; McGuire, AL; Lupski, J.R.; Gibbs, RA; Brown, Craig

doi:10.1111/j.1399-0004.2012.01951.x

Cited by 27 publications

(29 citation statements)

References 16 publications

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“…31,[33][34][35] In our study, we showed that the coverage of a predefined list of genes associated with dHMN and overlapping disorders was sufficiently high to use exome sequencing as an initial diagnostic approach. In addition, the combined use of Sequenom MassARRAY to validate the genetic variants identified appeared to be a fast and powerful strategy.…”

Section: Discussionmentioning

confidence: 84%

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

et al. 2013

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Distal hereditary motor neuropathies (dHMNs) are a heterogenous group of genetic disorders with length-dependent degeneration of motor axons. Obtaining a genetic diagnosis in patients with dHMN remains challenging. We performed exome sequencing in a diagnostic setting in 12 patients with a clinical diagnosis of dHMN. Potential disease-causing variants in genes associated with dHMN and other forms of inherited neuropathies/motor neuron diseases were validated using Sequenom. The coverage in the genes studied was 495% with an average coverage of 450 times. In none of the patients a mutations was found in genes previously reported to be associated with dHMN. However, in 2/12 patients a recessive mutation in histidine triad nucleotide binding protein 1 (HINT1, recently discovered as a cause of axonal neuropathy with neuromyotonia) was identified. Our results demonstrate the diagnostic value of exome sequencing for patients with inherited neuropathies. The phenotypic spectrum of recessive mutations in HINT1 includes dHMN. HINT1 should be added to the list of genes to check for in dHMN.

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Section: Discussionmentioning

confidence: 84%

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

et al. 2013

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“…CACNA1S pathogenic variants have been identified as the cause of hypokalemic periodic paralysis type 1 (HOKPP1) (Burge and Hanna 2012; Hanchard et al. 2013), but persistent weakness of the child is somewhat inconsistent with HOKPP1. While it has been suspected that CACNAS1 variants could cause myopathies due to the physical and mechanical coupling between its gene product, the voltage-dependent L-type calcium channel subunit alpha-1S (Cav1.1), and the Ryanodine receptor Ca 2+ release channel 1 (RYR-1)(Wu et al.…”

Section: Resultsmentioning

confidence: 92%

“…Pathogenic variants in CACNA1S have been identified as a cause of HOKPP1, but RYR1 have not (Burge and Hanna 2012; Hanchard et al. 2013). Pathogenic variants in RYR1 are the most common causes of CCD, while CACNA1S have not been identified as a cause of CCD (Wu et al.…”

Section: Discussionmentioning

confidence: 99%

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing

Hunter

Ahearn

Balak

et al. 2015

Molec Gen & Gen Med

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Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes.

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“…[6][7][8] Mutations in the mitochondrial alanyltRNA synthetase 2 gene (AARS2; OMIM *612035) have been found in severe infantile cardiomyopathy in 2 families. 9 In the present study, we describe a very different clinical picture determined by AARS2 genetic defects in 6 patients affected by a progressive leukoencephalopathy and, in females, ovarian failure, a clinical presentation previously described as "ovarioleukodystrophy."…”

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confidence: 99%

Novel (ovario) leukodystrophy related to AARS2 mutations

et al. 2014

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Objectives: The study was focused on leukoencephalopathies of unknown cause in order to define a novel, homogeneous phenotype suggestive of a common genetic defect, based on clinical and MRI findings, and to identify the causal genetic defect shared by patients with this phenotype.Methods: Independent next-generation exome-sequencing studies were performed in 2 unrelated patients with a leukoencephalopathy. MRI findings in these patients were compared with available MRIs in a database of unclassified leukoencephalopathies; 11 patients with similar MRI abnormalities were selected. Clinical and MRI findings were investigated.Results: Next-generation sequencing revealed compound heterozygous mutations in AARS2 encoding mitochondrial alanyl-tRNA synthetase in both patients. Functional studies in yeast confirmed the pathogenicity of the mutations in one patient. Sanger sequencing revealed AARS2 mutations in 4 of the 11 selected patients. The 6 patients with AARS2 mutations had childhoodto adulthood-onset signs of neurologic deterioration consisting of ataxia, spasticity, and cognitive decline with features of frontal lobe dysfunction. MRIs showed a leukoencephalopathy with striking involvement of left-right connections, descending tracts, and cerebellar atrophy. All female patients had ovarian failure. None of the patients had signs of a cardiomyopathy.Conclusions: Mutations in AARS2 have been found in a severe form of infantile cardiomyopathy in 2 families. We present 6 patients with a new phenotype caused by AARS2 mutations, characterized by leukoencephalopathy and, in female patients, ovarian failure, indicating that the phenotypic spectrum associated with AARS2 variants is much wider than previously reported.

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Exploring the utility of whole‐exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness

Cited by 27 publications

References 16 publications

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing

Novel (ovario) leukodystrophy related to AARS2 mutations

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