Just Expect It: Compound Heterozygous Variants of POMT1 in a Consanguineous Family—The Role of Next Generation Sequencing in Neuromuscular Disorders

2019 ◽  
Vol 51 (01) ◽  
pp. 072-075
Author(s):  
Maja von der Hagen ◽  
Lena-Luise Becker ◽  
Thomas F. Wienker ◽  
Martin Smitka ◽  
Luciana Musante ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Muscular Dystrophy ◽  
Neuromuscular Disorders ◽  
Brain Magnetic Resonance Imaging ◽  
Homozygosity Mapping ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Next Generation ◽  
Generation Sequencing

AbstractMuscular dystrophy-dystroglycanopathies (MDDG) are a group of genetically heterogeneous autosomal recessive disorders characterized by hypoglycosylation of α-dystroglycan. Here, we report on two female patients from a consanguineous Lebanese family that presented in early infancy with generalized muscle hypotonia and primary microcephaly. Brain magnetic resonance imaging (MRI) showed different degrees of hypoplasia of the cerebellar vermis and hypoplasia of corpus callosum. Muscle biopsy analyses revealed a muscular dystrophy with reduced expression of α-dystroglycan and merosin in immunoblot analyses. Homozygosity mapping failed to elucidate the causal mutation due to the accepted notion that, in consanguineous families, homozygote mutations cause disease. However, by applying whole exome sequencing, we identified a novel compound heterozygous POMT1 mutation that segregates with the phenotype and is in line with the clinical presentation. This underscores that a less expected compound heterozygous instead of homozygous mutation in a consanguineous marriage results in a recessive disorder and highlights the growing role of next generation sequencing in neuromuscular disorder diagnostics.

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

2018 ◽  
Vol 45 (3) ◽  
pp. 262-268 ◽  
Author(s):  
Lily Wu ◽  
Lauren Brady ◽  
John Shoffner ◽  
Mark A. Tarnopolsky
Keyword(s):  
Next Generation Sequencing ◽  
Muscular Dystrophy ◽  
Muscle Weakness ◽  
Neuromuscular Disorders ◽  
Cost Effective ◽  
Muscle Disease ◽  
Muscle Pathology ◽  
Next Generation ◽  
Pathogenic Variants ◽  
Generation Sequencing

AbstractBackground:Neuromuscular disorders are a phenotypically and genotypically diverse group of diseases that can be difficult to diagnose accurately because of overlapping clinical features and nonspecific muscle pathology. Next-generation sequencing (NGS) is a high-throughput technology that can be used as a more time- and cost-effective tool for identifying molecular diagnoses for complex genetic conditions, such as neuromuscular disorders.Methods:One hundred and sixty-nine patients referred to a Canadian neuromuscular clinic for evaluation of possible muscle disease were screened with an NGS panel of muscular dystrophy–associated genes. Patients were categorized by the reason of referral (1) muscle weakness (n=135), (2) recurrent episodes of rhabdomyolysis (n=18), or (3) idiopathic hyperCKemia (n=16).Results:Pathogenic and likely pathogenic variants were identified in 36.09% of patients (61/169). The detection rate was 37.04% (50/135) in patients with muscle weakness, 33.33% (6/18) with rhabdomyolysis, and 31.25% (5/16) in those with idiopathic hyperCKemia.Conclusions:This study shows that NGS can be a useful tool in the molecular workup of patients seen in a neuromuscular clinic. Evaluating the utility of large panels of a muscle disease-specific NGS panel to investigate the genetic susceptibilities of rhabdomyolysis and/or idiopathic hyperCKemia is a relatively new field. Twenty-eight of the pathogenic and likely pathogenic variants reported here are novel and have not previously been associated with disease.

scholarly journals Environmental Surveillance through Next-Generation Sequencing to Unveil the Diversity of Human Enteroviruses beyond the Reported Clinical Cases

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 120
Author(s):  
Andrés Lizasoain ◽  
Daiana Mir ◽  
Gisella Masachessi ◽  
Adrián Farías ◽  
Nélida Rodríguez-Osorio ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Next Generation ◽  
Echovirus 30 ◽  
Coxsackievirus B4 ◽  
Important Region ◽  
Enterovirus A71 ◽  
Wastewater Samples ◽  
Valuable Role ◽  
Generation Sequencing

The knowledge about circulation of Human Enteroviruses (EVs) obtained through medical diagnosis in Argentina is scarce. Wastewater samples monthly collected in Córdoba, Argentina during 2011–2012, and then in 2017–2018 were retrospectively studied to assess the diversity of EVs in the community. Partial VP1 gene was amplified by PCR from wastewater concentrates, and amplicons were subject of next-generation sequencing and genetic analyses. There were 41 EVs detected, from which ~50% had not been previously reported in Argentina. Most of the characterized EVs (60%) were detected at both sampling periods, with similar values of intratype nucleotide diversity. Exceptions were enterovirus A71, coxsackievirus B4, echovirus 14, and echovirus 30, which diversified in 2017–2018. There was a predominance of types from EV-C in 2017–2018, evidencing a common circulation of these types throughout the year in the community. Interestingly, high genetic similarity was evidenced among environmental strains of echovirus 30 circulating in 2011–2012 and co-temporal isolates obtained from patients suffering aseptic meningitis in different locations of Argentina. This study provides an updated insight about EVs circulating in an important region of South America, and suggests a valuable role of wastewater-based epidemiology in predicting outbreaks before the onset of cases in the community.

scholarly journals Next generation sequencing of RB1gene for the molecular diagnosis of ethnic minority with retinoblastoma in Yunnan

2020 ◽  
Author(s):  
Huaiyu Gu ◽  
Zhen Zhang ◽  
Yi-shuang Xiao ◽  
Ru Shen ◽  
Hong-chao Jiang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Low Income ◽  
Eastern China ◽  
Low Income Countries ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Bioinformatics Pipeline ◽  
Generation Sequencing

Abstract Background: Retinoblastoma is a rare intraocular malignancy and typically initiated by inactivating biallelic mutations of RB1 gene. Each year, ~8,000 children worldwide are diagnosed for retinoblastoma. In high-income countries, patient survival is over 95% while low-income countries is ~30%.If disease is diagnosed early and treated in centers specializing in retinoblastoma, the survival might exceed 95% and many eyes could be safely treated and support a lifetime of good vision. In China, approximate 1,100 newly diagnosed cases are expected annually and 28 hospitals covering 25 provinces established centers classified by expertise and resources for better treatment options and follow-up. Comparing with other province of eastern China, Yunnan province is remote geographically. This might result that healthcare staff have low awareness of the role of genetic testing in management and screening in families.Methods: The patients with retinoblastoma were selected in Yunnan. DNA from blood was used for targeted gene sequencing. Then, an in-house bioinformatics pipeline was done to detect both single nucleotide variants and small insertions/deletions. The pathogenic mutations were identified and further confirmed by conventional methods and cosegregation in families.Results: Using our approach, targeted next generation sequencing was used to detect the mutation of these 12 probands. Bioinformatic predictions showed that nine mutations were found in our study and four were novel pathogenic variants in these nine mutations.Conclusions: It’s the first report to describe RB1 mutations in Yunnan children with retinoblastoma. This study would improve role of genetic testing for management and family screening.

scholarly journals Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

2021 ◽  
Vol 11 ◽  
Author(s):  
Emilie Darrigues ◽  
Benjamin W. Elberson ◽  
Annick De Loose ◽  
Madison P. Lee ◽  
Ebonye Green ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Next Generation Sequencing ◽  
Precision Medicine ◽  
Critical Role ◽  
First Year ◽  
Histopathological Diagnosis ◽  
Next Generation ◽  
Cancer Predisposition Syndrome ◽  
Generation Sequencing

Neuro-oncology biobanks are critical for the implementation of a precision medicine program. In this perspective, we review our first year experience of a brain tumor biobank with integrated next generation sequencing. From our experience, we describe the critical role of the neurosurgeon in diagnosis, research, and precision medicine efforts. In the first year of implementation of the biobank, 117 patients (Female: 62; Male: 55) had 125 brain tumor surgeries. 75% of patients had tumors biobanked, and 16% were of minority race/ethnicity. Tumors biobanked were as follows: diffuse gliomas (45%), brain metastases (29%), meningioma (21%), and other (5%). Among biobanked patients, 100% also had next generation sequencing. Eleven patients qualified for targeted therapy based on identification of actionable gene mutations. One patient with a hereditary cancer predisposition syndrome was also identified. An iterative quality improvement process was implemented to streamline the workflow between the operating room, pathology, and the research laboratory. Dedicated tumor bank personnel in the department of neurosurgery greatly improved standard operating procedure. Intraoperative selection and processing of tumor tissue by the neurosurgeon was integral to increasing success with cell culture assays. Currently, our institutional protocol integrates standard histopathological diagnosis, next generation sequencing, and functional assays on surgical specimens to develop precision medicine protocols for our patients. This perspective reviews the critical role of neurosurgeons in brain tumor biobank implementation and success as well as future directions for enhancing precision medicine efforts.

scholarly journals Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 539
Author(s):  
Lidia Gonzalez-Quereda ◽  
Maria Jose Rodriguez ◽  
Jordi Diaz-Manera ◽  
Jorge Alonso-Perez ◽  
Eduard Gallardo ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Gene Panel ◽  
Muscular Dystrophies ◽  
Next Generation ◽  
Congenital Myasthenic Syndromes ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing ◽  
Myasthenic Syndromes

The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients’ clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.

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