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.

scholarly journals Clinical and Molecular Characterization of Qatari Patients with Inherited Dysfibrinogenemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1037-1037
Author(s):  
Amna Gameil ◽  
Hajer Al-Mulla ◽  
Aliaa Amer ◽  
Tawfeg Ben-Omran ◽  
Mohamed A Yassin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Clinical Phenotype ◽  
Pathogenic Mutation ◽  
Functional Assay ◽  
Sequencing Analysis ◽  
Thrombin Time ◽  
Whole Exome ◽  
Antigen Assay

Abstract Background and Objectives: Inherited Dysfibrinogenemia is a rare functional fibrinogen disorder in which the fibrinogen protein is present but with a reduced function. Fibrinogen is a 340-kDa glycoprotein that is encoded by three genes namely: Fibrinogen Bb (FGB), Aa (FGA), and g (FGG). The disorder is characterized by a wide spectrum of clinical phenotypes, ranging from asymptomatic to mild- to-severe bleeding or thrombotic manifestations and recurrent miscarriages. The mode of inheritance is mostly autosomal dominant manner and frequently as a result of a point mutation in FGA (Arg35) and FGG (Arg301). The laboratory diagnosis is based on discrepancy between fibrinogen antigen (detected by immunoassay or by immuno-turbidimetric assay) and functional assay (detected by Clauss method or other clot-based assays). The disorder is often associated with prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT).Fibrinogen activity is reduced by Clauss method while the antigen assay remains normal. The management is directed towards prevention of bleeding with prophylactic fibrinogen concentrates or cryoprecipitate prior to invasive procedures, surgeries or delivery. Dysfibrinogenemia is a rare disorder yet it is very prevalent in Qatar as a result of high rate of consanguineous marriages. The aim of our study is to describe the clinical phenotype in relation to genotype in this cohort. Methods We conducted a retrospective analysis of 23 patients with Inherited Dysfibrinogenemia reported by our center from 2015 to 2020 . Patients with a positive family of history fibrinogen disorder and abnormal coagulation screen, low functional fibrinogen assay (by Clauss method) or normal antigen level by turbidimetry were included. Whole exome sequencing (WES) was performed on the proband case which detected a likely pathogenic mutation that was tested on subsequent cases. We diagnosed our patients with Inherited Dysfibrinogenemia based on both coagulation-based assays and molecular tests. Probable Inherited Dysfibrinogenemia was considered in patients where the molecular test or antigen assay were not performed. To assess the clinical phenotype, data was collected that included; age at diagnosis, gender, bleeding and thrombotic events as well as coagulation screening. (Table 1) Results 23 patients who were described in this cohort belong to the same tribe. 74% (17 o/23) were female and only 41% (7/17) reported an obstetric bleeding (postpartum or post abortion) and one reported mild bleeding that occurred in the postmenopausal period and no previous bleeding (case#19). The median age of diagnosis was 28.8 years (5-69) for the females. All male cases in the cohort were detected either during routine screening or prior to surgery with no previous history of bleeding. No thrombotic events were observed in this cohort. Genetic Analysis Following proper genetic counseling and informed consent, whole exome sequencing analysis (WES) was performed on the index case which included testing of the fibrinogen genes FGA, FGB and FGG. WES revealed a likely pathogenic mutation in the FGA gene (p. Arg35His (R35H) (CGT>CAT): c.104 G>A in exon 2)-Located within the cleavage site of fibrinopeptide A by thrombin (The UniProt Consortium, 2017), which is a mutational hotspot. This result is likely consistent with the diagnosis of Dysfibrinogenemia. Conclusion The FGA R35H mutation is considered a probable recurrent variant in a large tribe in the Qatari population and is associated with late onset mild bleeding manifestations in minority of cases . Despite the fact that the reported tribe is highly consanguineous, the R35H mutation behaved in an autosomal dominant manner rather than recessive in this cohort.Further studies to assess phenotype - genotype correlation of Dysfibrinogenemia is warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

2019 ◽  
Vol 157 (3) ◽  
pp. 148-152 ◽  
Author(s):  
Liang-Liang Fan ◽  
Hao Huang ◽  
Jie-Yuan Jin ◽  
Jing-Jing Li ◽  
Ya-Qin Chen ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Dilated Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Pathogenic Mutation ◽  
Left Ventricular ◽  
Chinese Family ◽  
Whole Exome

Dilated cardiomyopathy (DCM) is a severe cardiovascular disease which can lead to heart failure and sudden cardiac death (SCD). The typical feature of DCM is left ventricular enlargement or dilatation. In some conditions, DCM and arrhythmia can occur concurrently, apparently promoting the prevalence of SCD. According to previous studies, mutations in more than 100 genes have been detected in DCM and/or arrhythmia patients. Here, we report a Chinese family with typical DCM, ventricular tachycardia, syncope, and SCD. Using whole-exome sequencing, a novel, likely pathogenic mutation (c.959T>G/p.L320R) of actinin alpha 2 (ACTN2) was identified in all affected family members. This novel mutation was also predicted to be disease-causing by MutationTaster, SIFT, and Polyphen-2. Our study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of the family, but also provides a new case with overlap phenotype that may be caused by the ACTN2 variant.

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.

scholarly journals NAPG mutation in family members with hereditary hemorrhagic telangiectasia in China

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yu Xu ◽  
Yong-Biao Zhang ◽  
Li-Jun Liang ◽  
Jia-Li Tian ◽  
Jin-Ming Lin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Sanger Sequencing ◽  
Conformational Stability ◽  
Sequencing Analysis ◽  
Large Pedigree ◽  
Whole Exome ◽  
Variant Filtering ◽  
Genetic Contributions

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. Methods We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. Results After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. Conclusions NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.

scholarly journals Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yahya Benbouchta ◽  
Imane Cherkaoui Jaouad ◽  
Habiba Tazi ◽  
Hamza Elorch ◽  
Mouna Ouhenach ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Symptoms ◽  
Age Of Onset ◽  
Novel Mutation ◽  
Corneal Dystrophy ◽  
Heterozygous Mutation ◽  
Large Variability ◽  
Whole Exome ◽  
Moroccan Family

Abstract Background Corneal dystrophies (CDs) are a heterogeneous group of bilateral, genetically determined, noninflammatory bilateral corneal diseases that are usually limited to the cornea. CD is characterized by a large variability in the age of onset, evolution and visual impact and the accumulation of insoluble deposits at different depths in the cornea. Clinical symptoms revealed bilateral multiple superficial, epithelial, and stromal anterior granular opacities in different stages of severity among three patients of this family. A total of 99 genes are involved in CDs. The aim of this study was to identify pathogenic variants causing atypical corneal dystrophy in a large Moroccan family and to describe the clinical phenotype with severely different stages of evolution. Case presentation In this study, we report a large Moroccan family with CD. Whole-exome sequencing (WES) was performed in the three affected members who shared a phenotype of corneal dystrophy in different stages of severity. Variant validation and familial segregation were performed by Sanger sequencing in affected sisters and mothers and in two unaffected brothers. Whole-exome sequencing showed a novel heterozygous mutation (c.1772C > A; p.Ser591Tyr) in the TGFBI gene. Clinical examinations demonstrated bilaterally multiple superficial, epithelial and stromal anterior granular opacities in different stages of severity among three patients in this family. Conclusions This report describes a novel mutation in the TGFBI gene found in three family members affected by different phenotypic aspects. This mutation is associated with Thiel-Behnke corneal dystrophy; therefore, it could be considered a novel phenotype genotype correlation, which will help in genetic counselling for this family.

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