scholarly journals Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Amjad Khan ◽  
Rongrong Wang ◽  
Shirui Han ◽  
Muhammad Umair ◽  
Safdar Abbas ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Limb Girdle Muscular Dystrophy ◽  
Molecular Diagnostic ◽  
Sequencing Analysis ◽  
Whole Exome

Abstract Background Limb-girdle muscular dystrophies (LGMDs) are large group of heterogeneous genetic diseases, having a hallmark feature of muscle weakness. Pathogenic mutations in the gene encoding the giant skeletal muscle protein titin (TTN) are associated with several muscle disorders, including cardiomyopathy, recessive congenital myopathies and limb-girdle muscular dystrophy (LGMD) type10. The phenotypic spectrum of titinopathies is expanding, as next generation sequencing (NGS) technology makes screening of this large gene possible. Aim This study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive LGMD type 10. Methods DNA from peripheral blood samples were obtained, whole exome sequencing (WES) was performed and several molecular and bioinformatics analysis were conducted to identify the pathogenic variant. TTN coding and near coding regions were further amplified using PCR and sequenced via Sanger sequencing. Results Whole exome sequencing analysis revealed a novel homozygous missense variant (c.98807G > A; p.Arg32936His) in the TTN gene in the index patients. No heterozygous individuals in the family presented LGMD features. The variant p.Arg32936His leads to a substitution of the arginine amino acid at position 32,936 into histidine possibly causing LGMD type 10. Conclusion We identified a homozygous missense variant in TTN, which likely explains LGMD type 10 in this family in line with similar previously reported data. Our study concludes that WES is a successful molecular diagnostic tool to identify pathogenic variants in large genes such as TTN in highly inbred population.

scholarly journals Limb-girdle muscular dystrophy due to a novel homozygous ISPD gene mutation disclosed by whole exome sequencing

2015 ◽  
Vol 357 ◽  
pp. e339
Author(s):  
V. Mastorodemos ◽  
E. Vogiatzi ◽  
H. Latsoudis ◽  
P. Vorgia ◽  
G. Amoiridis ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Exome Sequencing ◽  
Gene Mutation ◽  
Whole Exome Sequencing ◽  
Limb Girdle Muscular Dystrophy ◽  
Whole Exome

scholarly journals Whole exome sequencing reveals a homozygous SGCB variant in a Pakhtun family with limb girdle muscular dystrophy (LGMDR4) phenotype

Gene Reports ◽  
2021 ◽  
Vol 22 ◽  
pp. 101014
Author(s):  
Muhammad Tariq ◽  
Muhammad Latif ◽  
Memona Inam ◽  
Amin Jan ◽  
Nousheen Bibi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Limb Girdle Muscular Dystrophy ◽  
Whole Exome

scholarly journals Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy

2015 ◽  
Vol 72 (12) ◽  
pp. 1424 ◽  
Author(s):  
Roula Ghaoui ◽  
Sandra T. Cooper ◽  
Monkol Lek ◽  
Kristi Jones ◽  
Alastair Corbett ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Limb Girdle Muscular Dystrophy ◽  
Whole Exome

scholarly journals Clinical Whole-Exome Sequencing Analysis Reveals a Novel Missense COL11A1 Mutation Resulting in an 18-Week Iranian Male Aborted Fetus with Fibrochondrogenesis 1: A Case Report

2021 ◽  
Author(s):  
Hanifeh Mirtavoos-Mahyari ◽  
Sanaz Ajami ◽  
Amirhosein Mehrtash ◽  
Seyedeh Mahya Marashiyan ◽  
Farbod Bahreini ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Missense Variant ◽  
Pathogenic Mutation ◽  
Sequencing Analysis ◽  
Gene Encoding ◽  
Protein Levels ◽  
Proper Role ◽  
Whole Exome

Abstract BackgroundFibrochondrogenesis 1, an autosomal recessive syndrome, is an infrequent and rare disease, causing short-limbed skeletal dysplasia. This syndrome is clinically characterized and distinguished by a small nose and anteverted bares, flat midface, shortened long bones, and a protuberant abdomen. Mutations in the gene encoding the α1 chain of type XI collagen (COL11A1) are seen to be the main cause of this disease.Case PresentationWe present an 18-week Iranian male aborted fetus with Fibrochondrogenesis 1 from consanguineous parents. Whole-exome sequencing (WES) revealed a novel missense variant from G to A in exon 45 of 68 in the COL11A1 gene (NM_080629.2: c.3440G>A, [p.G1147E, g.103404625]). The mutation was confirmed by Sanger sequencing and further, MutationTaster predicted this variant to be disease-causing.ConclusionBioinformatic analysis suggests that this variant is highly conserved in both nucleotide and protein levels, suggesting that it has an important function in the proper role of COL11A1 protein. In-silico analysis suggests that this mutation alters the COL11A1 protein structure through a Glycine to Glutamic acid substitution. This is a novel mutation and a rare variant as this variant is not reported in gmomAD, ExAC, or 1000 genome databases.To the best of the authors’ knowledge, this is the first study to report a novel pathogenic mutation in COL11A1 in association with Fibrochondrogenesis 1. Therefore, we suggest that WES can be used as a robust method to achieve rapid diagnosis and identification of pathogenic and novel mutations in patients.

Specific Cognitive Changes due to Hippocalcin Alterations? A Novel Familial Homozygous Hippocalcin Variant Associated with Inherited Dystonia and Altered Cognition

2021 ◽  
Author(s):  
Sandy Siegert ◽  
Wolfgang M. Schmidt ◽  
Thomas Pletschko ◽  
Reginald E. Bittner ◽  
Sonja Gobara ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Pediatric Patient ◽  
Autosomal Recessive ◽  
Family Members ◽  
Missense Variant ◽  
Index Patient ◽  
Cognitive Changes ◽  
Her Family ◽  
Whole Exome

Abstract Background Recent research suggested an hippocalcin (HPCA)-related form of DYT2-like autosomal recessive dystonia. Two reports highlight a broad spectrum of the clinical phenotype. Here, we describe a novel HPCA gene variant in a pediatric patient and two affected relatives. Methods Whole exome sequencing was applied after a thorough clinical and neurological examination of the index patient and her family members. Results of neuropsychological testing were analyzed. Results Whole exome sequencing revealed a novel homozygous missense variant in the HPCA gene [c.182C>T p.(Ala61Val)] in our pediatric patient and the two affected family members. Clinically, the cases presented with dystonia, dysarthria, and jerky movements. We observed a particular cognitive profile with executive dysfunctions in our patient, which corresponds to the cognitive deficits that have been observed in the patients previously described. Conclusion We present a novel genetic variant of the HPCA gene associated with autosomal recessive dystonia in a child with childhood-onset dystonia supporting its clinical features. Furthermore, we propose specific HPCA-related cognitive changes in homozygous carriers, underlining the importance of undertaking a systematic assessment of cognition in HPCA-related dystonia.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

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