scholarly journals Molecular Investigation of Iranian Patients Suspected to Hereditary Spherocytosis

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Shahab-Movahed Z ◽  
◽  
Majd A ◽  
Torbati ES ◽  
Zeinali S ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Hereditary Spherocytosis ◽  
Diagnostic Yield ◽  
Gene Mutations ◽  
Causative Variant ◽  
Rbc Membrane ◽  
Whole Exome ◽  
Molecular Investigation ◽  
Moderate Anemia ◽  
Iranian Patients

Introduction: Hereditary spherocytosis is a heterogeneous disorder with mild to moderate anemia. The aim of this study was to evaluate the inherited spherocytosis gene mutations in patients with RBC cytoplasmic disorders in Iranian population. Materials and Methods: In this study, Whole Exome Sequencing (WES) was performed for patients suspected to hereditary spherocytosis and their relatives. Results: Sequence analysis of the probands and their parents identified variations in ANK1 gene (NM_001142446.1:c.127-2A>G), SPTB (c. 14delC, p.Thr5LysfsTer41), SPTA1 (c.466C>T), SLC4A1 (c.2494C>T) and SLC25A38 gene (c.683G>T, NP_060345.2:p.Gly228Val that could be related to the patients clinical manifestation. Conclusion: Findings are in line with the appropriate diagnostic yield of WES in determining the causative variant especially in those disorders that many genes are involved like anemia. This is the first report of a cohort of Iranian patients with anemia suspected to that were investigated using WES technology. Further studies are needed to investigate the distribution of gene mutations in patients with RBC membrane disorders in Iran

scholarly journals One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Robert Meyer ◽  
Matthias Begemann ◽  
Christian Thomas Hübner ◽  
Daniela Dey ◽  
Alma Kuechler ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Uniparental Disomy ◽  
Molecular Testing ◽  
Main Body ◽  
Comprehensive Overview ◽  
Maternal Uniparental Disomy ◽  
Whole Exome ◽  
Silver Russell Syndrome

Abstract Background Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented. Main body We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS. Conclusions WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

scholarly journals Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals The identification of novel gene mutations for degenerative lumbar spinal stenosis using whole-exome sequencing in a Chinese cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xin Jiang ◽  
Dong Chen
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Spinal Stenosis ◽  
Lumbar Spinal Stenosis ◽  
Gene Mutations ◽  
Specific Gene ◽  
Single Nucleotide ◽  
Degenerative Lumbar Spinal Stenosis ◽  
Whole Exome ◽  
Lumbar Spinal

Abstract Background Degenerative lumbar spinal stenosis (DLSS) is a common lumbar disease that requires surgery. Previous studies have indicated that genetic mutations are implicated in DLSS. However, studies on specific gene mutations are scarce. Whole-exome sequencing (WES) is a valuable research tool that identifies disease-causing genes and could become an effective strategy to investigate DLSS pathogenesis. Methods From January 2016 to December 2017, we recruited 50 unrelated patients with symptoms consistent with DLSS and 25 unrelated healthy controls. We conducted WES and exome data analysis to identify susceptible genes. Allele mutations firstly identified potential DLSS variants in controls to the patients’ group. We conducted a site-based association analysis to identify pathogenic variants using PolyPhen2, SIFT, Mutation Taster, Combined Annotation Dependent Depletion, and Phenolyzer algorithms. Potential variants were further confirmed using manual curation and validated using Sanger sequencing. Results In this cohort, the major classification variant was missense_mutation, the major variant type was single nucleotide polymorphism (SNP), and the major single nucleotide variation was C > T. Multiple SNPs in 34 genes were identified when filtered allele mutations in controls to retain only patient mutations. Pathway enrichment analyses revealed that mutated genes were mainly enriched for immune response-related signaling pathways. Using the Novegene database, site-based associations revealed several novel variants, including HLA-DRB1, PARK2, ACTR8, AOAH, BCORL1, MKRN2, NRG4, NUP205 genes, etc., were DLSS related. Conclusions Our study revealed that deleterious mutations in several genes might contribute to DLSS etiology. By screening and confirming susceptibility genes using WES, we provided more information on disease pathogenesis. Further WES studies incorporating larger DLSS patient cohorts are required to comprehend the genetic landscape of DLSS pathophysiology fully.

scholarly journals Whole-exome mutational landscape of neuroendocrine carcinomas of the gallbladder

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Fatao Liu ◽  
Yongsheng Li ◽  
Dongjian Ying ◽  
Shimei Qiu ◽  
Yong He ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Large Cell ◽  
Molecular Signatures ◽  
Single Nucleotide Variants ◽  
Oncogenic Signaling ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Deadly Disease ◽  
Oncogenic Signaling Pathways ◽  
Neuroendocrine Carcinomas

AbstractNeuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) is a rare but extremely malignant subtype of gallbladder cancer (GBC). The genetic and molecular signatures of GB-NEC are poorly understood; thus, molecular targeting is currently unavailable. In the present study, we applied whole-exome sequencing (WES) technology to detect gene mutations and predicted somatic single-nucleotide variants (SNVs) in 15 cases of GB-NEC and 22 cases of general GBC. In 15 GB-NECs, the C > T mutation was predominant among the 6 types of SNVs. TP53 showed the highest mutation frequency (73%, 11/15). Compared with neuroendocrine carcinomas of other organs, significantly mutated genes (SMGs) in GB-NECs were more similar to those in pulmonary large-cell neuroendocrine carcinomas (LCNECs), with driver roles for TP53 and RB1. In the COSMIC database of cancer-related genes, 211 genes were mutated. Strikingly, RB1 (4/15, 27%) and NAB2 (3/15, 20%) mutations were found specifically in GB-NECs; in contrast, mutations in 29 genes, including ERBB2 and ERBB3, were identified exclusively in GBC. Mutations in RB1 and NAB2 were significantly related to downregulation of the RB1 and NAB2 proteins, respectively, according to immunohistochemical (IHC) data (p values = 0.0453 and 0.0303). Clinically actionable genes indicated 23 mutated genes, including ALK, BRCA1, and BRCA2. In addition, potential somatic SNVs predicted by ISOWN and SomVarIUS constituted 6 primary COSMIC mutation signatures (1, 3, 30, 6, 7, and 13) in GB-NEC. Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch, WNT, Hippo, and RTK-RAS pathways. In summary, we have systematically identified the mutation landscape of GB-NEC, and these findings may provide mechanistic insights into the specific pathogenesis of this deadly disease.

scholarly journals A Case Report of a Prenatally Missed Mowat-Wilson Syndrome With Isolated Corpus Callosum Agenesis

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110065
Author(s):  
Nesrin Şenbil ◽  
Zeynep Arslan ◽  
Derya Beyza Sayın Kocakap ◽  
Yasemin Bilgili
Keyword(s):  
Corpus Callosum ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Gene Mutations ◽  
Hirschsprung Disease ◽  
Agenesis Of Corpus Callosum ◽  
Whole Exome ◽  
Congenital Cardiac Anomalies ◽  
History Of ◽  
Gene Mutation Analysis

Mowat–Wilson syndrome (MWS) is an autosomal dominant genetic disorder caused by ZEB2 gene mutations, manifesting with unique facial characteristics, moderate to severe intellectual problems, and congenital malformations as Hirschsprung disease, genital and ophthalmological anomalies, and congenital cardiac anomalies. Herein, a case of 1-year-old boy with isolated agenesis of corpus callosum (IACC) in the prenatal period is presented. He was admitted postnatally with Hirschsprung disease (HSCR), hypertelorism, uplifted earlobes, deeply set eyes, frontal bossing, oval-shaped nasal tip, ‘‘M’’ shaped upper lip, opened mouth and prominent chin, and developmental delay. Hence, MWS was primarily considered and confirmed by the ZEB2 gene mutation analysis. His karyotype was normal. He had a history of having a prenatally terminated brother with similar features. Antenatally detected IACC should prompt a detailed investigation including karyotype and microarray; even if they are normal then whole exome sequencing (WES) should be done.

Novel Recurrent Altered Genes in Chinese Patients With Anaplastic Thyroid Cancer

2021 ◽  
Author(s):  
Lingyun Zhang ◽  
Zhixiang Ren ◽  
Zhengzheng Su ◽  
Yang Liu ◽  
Tian Yang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Copy Number ◽  
Treatment Strategies ◽  
Gene Mutations ◽  
Anaplastic Thyroid Cancer ◽  
Chinese Patients ◽  
Driver Gene ◽  
Phosphatidylinositol 3 Kinase ◽  
Entire Cohort ◽  
Whole Exome

Abstract Background Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy, and few systematic investigations on genomic profiles of ATC have been performed in Chinese patients. Methods Fifty-four ATC patients in West China Hospital between 2010 to 2020 were retrospectively analyzed, while 29 patients with available samples were sequenced by whole-exome sequencing (WES). The associations between genomic alterations and clinical characteristics were statistically evaluated. Results The median overall survival was 3.0 months in the entire cohort, which was impacted by multiple clinical features, including age, tumor size, and different treatment strategies. In the WES cohort, totally 797 nonsilent mutations were detected; the most frequently altered genes were TP53 (48%), BRAF (24%), PIK3CA (24%), and TERT promoter (21%). Although these mutations have been well-reported in previous studies, ethnic specificity was exhibited in terms of mutation frequency. Moreover, several novel significantly mutated genes were identified including RBM15 (17%), NOTCH2NL (14%), CTNNA3 (10%), and KATNAL2 (10%). WES-based copy number alteration analysis also revealed a high frequent gain of NOTCH2NL (41%), which induced its increased expression. Gene mutations and copy number alterations were enriched in phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin (mTOR), NOTCH, and WNT pathways. Conclusions This study reveals shared and ethnicity-specific genomic profiles of ATC in Chinese patients and suggests NOTCH2NL may act as a novel candidate driver gene for ATC tumorigenesis.

scholarly journals Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease

2017 ◽  
Vol 3 (5) ◽  
pp. e177 ◽  
Author(s):  
Javier Ruiz-Martínez ◽  
Luis J. Azcona ◽  
Alberto Bergareche ◽  
Jose F. Martí-Massó ◽  
Coro Paisán-Ruiz
Keyword(s):  
Parkinson Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genome Wide Association Study ◽  
Single Gene ◽  
Gene Mutations ◽  
Complement Control Protein ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

scholarly journals Contribution of Genetic and Environmental Risk Factors in a Juvenile Idiopathic Arthritis Large Family With SERPINA1 Gene Mutations

2021 ◽  
Author(s):  
Cyprian Popescu
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Gene Mutations ◽  
Large Family ◽  
Carrier Status ◽  
Multiplex Family ◽  
Serpina1 Gene ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Genetic And Environmental Factors ◽  
Underlying Mechanisms

Abstract Objectives Although the underlying mechanisms and mediators of arthritis in juvenile idiopathic arthritis (JIA) are not well understood, accumulated evidence supports the mixt role of genetic and environmental factors. Few reports of multiplex families with JIA were published until now. The aim of this study was to identify new genetic or environmental associations concerning the patients of a kindred with juvenile idiopathic arthritis and psoriatic features (JIAPs). Methods Here, we characterized an extended multiplex family of 5 patients with juvenile idiopathic arthritis and psoriatic features (PsA) at the clinical and genetic level, using whole exome sequencing. Results We did not confirm in our family the linkage with the genetic factors already described that might be associated with increase susceptibility to JIA. We found a carrier status of siblings who inherited a pathogenic allele of the SERPINA1 gene from their mother who herself has two heterozygous pathogenic variants in the SERPINA1 gene. Conclusions Our data showed that JIA results from pleiotropic effects of environmental background with an only minor monogenic contribution. Even that a monogenetic factor could not be proved, some genetic factor as SERPINA1 mutations which can sensitize for psoriatic arthritis development seems to be involved. Further investigation must be done to prove whether SERPINA1 mutations may have a potential JIA causality.

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