scholarly journals Genotype–phenotype correlation of 17 cases of Pompe disease in Spanish patients and identification of 4 novel GAA variants

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Paula Hernández-Arévalo ◽  
José D. Santotoribio ◽  
Rocío Delarosa-Rodríguez ◽  
Antonio González-Meneses ◽  
Salvador García-Morillo ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Genetic Variants ◽  
European Population ◽  
Exercise Intolerance ◽  
Phenotype Correlation ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation ◽  
C 32 ◽  
Generation Sequencing ◽  
Worse Prognosis

Abstract Background Pompe disease (PD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the acid α-glucosidase gene (GAA) that produces defects in the lysosomal acid α-1,4-glucosidase. We aimed to identify genetic variations and clinical features in Spanish subjects to establish genotype–phenotype correlation. Methods A total of 2637 samples of patients who showed symptoms or susceptible signs of PD were enrolled in this observational study. Enzymatic activity was detected by fluorometric techniques and the genetic study was carried out using Next-Generation Sequencing. Results Fourteen different variants from 17 diagnosed patients were identified, seven males and nine females with LOPD (mean age 36.07, SD 20.57, range 7–64) and a 2-day-old boy with IOPD, four genetic variants had not been described in the literature previously, including a homozygous variant. In all of them α-glucosidase activity was decreased. Muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia and myalgia were commonly observed in patients. Conclusions This study report four new genetic variants that contribute to the pathogenic variants spectrum of the GAA gene. We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T>G being the most prevalent variant. Furthermore, it was confirmed that the c.236_246delCCACACAGTGC pathogenic variant in homozygosity is associated with early disease and a worse prognosis.

scholarly journals Genotype-Phenotype correlation of 17 cases of Pompe Disease in Spanish Patients and Identification of 4 Novel Mutations

2020 ◽  
Author(s):  
Paula Hernandez-Arevalo ◽  
Jose D. Santotoribio ◽  
Rocio Delarosa-Rodriguez ◽  
Antonio Gonzalez-Meneses ◽  
Salvador Garcia-Morillo ◽  
...  
Keyword(s):  
Pompe Disease ◽  
European Population ◽  
Exercise Intolerance ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation ◽  
C 32 ◽  
Gaa Gene ◽  
Generation Sequencing ◽  
Worse Prognosis ◽  
New Mutations

Abstract Background: Pompe disease (PD) is an autosomal recessive metabolic disorder caused by mutations in the acid α-glucosidase gene (GAA) that produces defects in the lysosomal acid α-1,4-glucosidase. We aimed to identify genetic variations and clinical features in Spanish subjects to establish genotype-phenotype correlation.Methods: A total of 2709 subjects who showed symptoms or susceptible signs of PD were enrolled in this observational study. Enzymatic activity was detected by fluorometric techniques and the genetic study was carried out using Next-Generation Sequencing.Results: Fourteen different variants from seventeen patients were identified, four of whom had not been described in the literature previously, including a homozygous variant. In all of them α-glucosidase activity was decreased. Muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia and myalgia were commonly observed in patients. Conclusions: This study report four new mutations that contribute to the mutation spectrum of the GAA gene. We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T> G being the most prevalent variant. Furthermore, it was confirmed that the c.236_246delCCACACAGTGC mutation in homozygosis is associated with early disease and a worse prognosis.

The genotype-phenotype correlation in Pompe disease

2012 ◽  
Vol 160C (1) ◽  
pp. 59-68 ◽  
Author(s):  
Marian Kroos ◽  
Marianne Hoogeveen-Westerveld ◽  
Ans van der Ploeg ◽  
Arnold J.J. Reuser
Keyword(s):  
Pompe Disease ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation

scholarly journals Sorting Rare ALS Genetic Variants by Targeted Re-Sequencing Panel in Italian Patients: OPTN, VCP, and SQSTM1 Variants Account for 3% of Rare Genetic Forms

2020 ◽  
Vol 9 (2) ◽  
pp. 412 ◽  
Author(s):  
Viviana Pensato ◽  
Stefania Magri ◽  
Eleonora Dalla Bella ◽  
Pierpaola Tannorella ◽  
Enrica Bersano ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Next Generation Sequencing Technology ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Rare Gene ◽  
Motor Neuron Loss ◽  
Generation Sequencing ◽  
Lateral Sclerosis ◽  
Diagnostic Investigations

Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease due to motor neuron loss variably associated with frontotemporal dementia (FTD). Next generation sequencing technology revealed an increasing number of rare and novel genetic variants and interpretation of their pathogenicity represents a major challange in the diagnosis of ALS. We selected 213 consecutive patients with sporadic or familial (16%) ALS, tested negative for SOD1, FUS, TARDBP, and C9orf72 mutations. To reveal rare forms of genetic ALS, we performed a comprehensive multi-gene panel screening including 46 genes associated with ALS, hereditary motor neuronopathies, spastic paraplegia, and FTD. Our study allowed the identification of pathogenic or likely pathogenic variants in 4.2% of patients. The genes with the highest percentage of pathogenic variants were OPTN (1%), VCP (1%) SQSTM1(1%), SETX (0.4%), FIG4 (0.4%), and GARS1 (0.4%) genes. We also found 49 novel or rare gene variants of unknown significance in 30 patients (14%), 44 unlikely pathogenic variants (39%), and 48 variants in ALS susceptibility genes. The results of our study suggest the screening of OPTN, VCP, and SQSTM1 genes in routine diagnostic investigations for both sporadic and familial cases, and confirm the importance of diagnosis and couselling for patients and their relative family members.

scholarly journals Molecular profiling of congenital glioblastoma using a next-generation sequencing panel

2021 ◽  
Author(s):  
Débora Cabral de Carvalho Corrêa ◽  
Francine Tesser-Gamba ◽  
Nasjla da Silva ◽  
Andrea Capellano ◽  
Maria Teresa Alves ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Variants ◽  
Next Generation ◽  
Congenital Brain Tumor ◽  
Molecular Alterations ◽  
Pathogenic Variants ◽  
Pediatric Neoplasms ◽  
Tumor Entity ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Background Congenital GBM (cGBM), presenting prenatally or within the first months of life, is among the rarest type of congenital brain tumor, with approximately 120 cases reported. Due to its infrequent occurrence, few studies have focused on the molecular and genetic aspects of this tumor, and the mutational events involved in the pathogenesis and progression of cGBM still remains poorly understood. This study aimed to investigate molecular alterations, with a potential prognostic marker and therapeutic target in cGBM using the next-generation sequencing (NGS) strategy. Methods We selected seven tumor samples from patients diagnosed with cGBM and treated at Pediatric Oncology Institute-GRAACC/UNIFESP. NGS was performed to identify somatic genetic variants in tumor samples using the Oncomine Childhood Cancer Research Assay panel, from ThermoFisher Scientific, designed specifically for pediatric neoplasms. Results Of all seven patients analyzed, three patients exhibited tumors with genetic variants, which include two pathogenic variants in NF1 and SUZ12 genes that have not been reported in cGBM yet, an increase in the number of copies of ALK gene, and two gene fusions, PPP1CB-ALK and TPM3-NTRK1. Also, none of the cases showed variants in H3F3A, TP53 and ATRX genes, alterations which are frequently seen in pediatric and adolescent GBM. Conclusions Our results suggest that cGBM may comprise a unique tumor entity and alterations in ALK and NTRK genes provide a potential target for therapy. Therefore, identification of genetic variants in cGBM is highly relevant in order to define prognosis and therapeutic strategies.

scholarly journals Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome

2021 ◽  
Author(s):  
Rie Asada Kitamura ◽  
Kristina Maxwell ◽  
Wenjuan Ye ◽  
Kelly Kries ◽  
Cris Brown ◽  
...  
Keyword(s):  
Stem Cell ◽  
Correlation Analysis ◽  
Combination Treatment ◽  
Disease Model ◽  
Wolfram Syndrome ◽  
Phenotype Correlation ◽  
Chemical Chaperones ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation ◽  
Therapeutic Development

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Stem cell-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulates genotype-related Wolfram phenotypes, which are milder than those of SC-islets with compound heterozygous WFS1 c.1672C>T (p.R558C), c.2654C>T (p.P885L). Enhancing residual WFS1 function by a combination treatment of chemical chaperones, sodium 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and restored SC-islet function. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient stem cell-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.

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