scholarly journals Common Variable Immunodeficiency with Genetic Defects Identified by Whole Exome Sequencing

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Ran Li ◽  
Yali Zheng ◽  
Yuqian Li ◽  
Rongbao Zhang ◽  
Fang Wang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Common Variable Immunodeficiency ◽  
Respiratory Infections ◽  
Genetic Diagnosis ◽  
Genetic Defects ◽  
Compound Heterozygous ◽  
Recurrent Respiratory Infections ◽  
Whole Exome ◽  
Common Variable

Common variable immunodeficiency (CVID) belongs to the primary immunodeficiency disorders (PIDs), presenting a profound heterogeneity in phenotype and genotype, with monogenic or complex causes. Recurrent respiratory infections are the most common clinical manifestations. CVID patients can also develop various autoimmune and lymphoproliferative complications. Genetic testing such as whole exome sequencing (WES) can be utilized to investigate likely genetic defects, helping for better clinical management. We described the clinical phenotypes of three sporadic cases of CVID, who developed recurrent respiratory infections with different autoimmune and lymphoproliferative complications. WES was applied to screen disease-causing or disease-associated mutations. Two patients were identified to have monogenic disorders, with compound heterozygous mutations in LRBA for one patient and a frameshift insertion in NFKB1 for another. The third patient was identified to be a complex form of CVID. Two novel mutations were identified, respectively, in LRBA and NFKB1. A combination of clinical and genetic diagnosis can be more extensively utilized in the clinical practice due to the complexity and heterogeneity of CVID.

scholarly journals Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency

2016 ◽  
Vol 7 ◽  
Author(s):  
Patrick Maffucci ◽  
Charles A. Filion ◽  
Bertrand Boisson ◽  
Yuval Itan ◽  
Lei Shang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Common Variable Immunodeficiency ◽  
Genetic Diagnosis ◽  
Whole Exome ◽  
Common Variable

scholarly journals Whole exome sequencing reveals a novel LRBA mutation and clonal hematopoiesis in a common variable immunodeficiency patient presented with hemophagocytic lymphohistiocytosis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yanling Ren ◽  
Feng Xiao ◽  
Fei Cheng ◽  
Xin Huang ◽  
Jianhu Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Common Variable Immunodeficiency ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Great Promise ◽  
Hematopoietic Stem ◽  
Genetic Method ◽  
Clonal Hematopoiesis ◽  
Whole Exome ◽  
Common Variable

AbstractCommon variable immunodeficiency (CVID) was a kind of primary immunodeficiency disorders with heterogeneous phenotype and genotype. Lipopolysaccharide-responsive and beige-like anchor (LRBA) mutation was identified as disease associated in CVID, advanced genetic method will help to detect atypical cases. We report a case of adult patient manifested as hemophagocytic lymphohistiocytosis (HLH), bone marrow examination suggested prosperity to MDS, manifested as increased immature myeloid cells and dysplastic hematopoiesis. Whole exome sequencing (WES) identified a novel heterogeneous c.1876T > C (p.W626R) mutation in LRBA and four somatic mutations: ASXL1 (c.1967dupA); PTPN11 (c.226G > A), U2AF1 (c.101C > T and c.470A > G), among which ASXL1 was a high-risk marker of clonal hematopoiesis. Combined with her recurrent severe infections and immune abnormalities such as hypoimmunoglobulinemia, the patient was diagnosed with CVID. Subsequent hematopoietic stem cell transplantation saved her from severe cytopenia and immune deficiency. This case report highlights the great promise of utilization of WES for diagnosing rare disease with atypical manifestations and guiding further treatment.

scholarly journals Integrated whole exome sequencing and functional approach delineate genetic heterogeneity in cerebellar ataxias

2021 ◽  
Author(s):  
Renu Kumari ◽  
Bharath Ram Uppilli ◽  
Sunil Shakya ◽  
Ajay Garg ◽  
Aditi Joshi ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Exome Sequencing ◽  
Cell Line ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Whole Exome ◽  
Cerebellar Ataxias ◽  
Disease Signatures

Abstract PurposeDisease deconvolution in heterogeneous cerebellar ataxias (CAs) needs a focussed approach to overcome the diagnostic challenges. A diverse clinical presentation with over 100 reported genetic loci, in addition to the various challenges associated with genotype-phenotype correlation complicate the genetic diagnosis in 40-60% of the CA cases that remain uncharacterized. We present here an integrated whole exome sequencing combined with a functional validation approach to delineate the genetic etiology in Indian CA patients.MethodA total of 50 familial and sporadic progressive CA families (negative for CNG expansion) including 101 subjects were recruited for this study. Index patients from 50 families were subjected to singleton whole exome sequencing (S-WES). Family-based WES (F-WES) was carried out for seven S-WES selected families. Protein simulation and docking studies were performed for seven genetic variants identified through WES. A Cell line-based model was used to assess disease signatures for variants in KCNC3 and a new candidate gene, SPTB.ResultsClinically relevant variants identified in 70% (35/50) of the selected families. We achieved a 50% (25/50) definitive diagnostic yield and 14% (7/50) probable diagnostic yield while 6% (3/50) of the families showed variants of uncertain significance. We prioritized compound heterozygous variants in a candidate gene, SPTB for cerebellar ataxia with hereditary spherocytosis. Lymphoblastoid cell line derived from a patient with a KCNC3 variant showed altered disease signatures with induced ROS and elevated unfolded protein response markers at the basal level.ConclusionOur results highlight an extensive experimental design for the genetic diagnosis of CA. Through targeted analysis of ataxia phenotype-derived gene panel in S-WES, new gene identification through F-WES, and revaluation of unsolved families’ WES data, we identified novel, reported and other clinically relevant variants in CA patients. Bioinformatic protein modeling along with the cellular insights into the pathogenicity of novel variants enabled delineation of genetic diagnostics and enhanced the mechanistic understanding of CAs.

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 Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Somayeh Khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh-Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods. Methods This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects. Conclusion In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.

Identification of Two Novel Mutations in PKHD1 Gene from Two Families with Polycystic Kidney Disease by Whole Exome Sequencing

2021 ◽  
Vol 22 ◽  
Author(s):  
Masoud Heidari ◽  
Hamid Gharshasbi ◽  
Alireza Isazadeh ◽  
Morteza Soleyman-Nejad ◽  
Mohammad Hossein Taskhiri ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Exome Sequencing ◽  
Polycystic Kidney Disease ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Genetic Alterations ◽  
Polycystic Kidney ◽  
Novel Mutations ◽  
Whole Exome

Background:: Polycystic kidney disease (PKD) is an autosomal recessive disorder resulting from mutations in the PKHD1 gene on chromosome 6 (6p12), a large gene spanning 470 kb of genomic DNA. Objective: The aim of the present study was to report newly identified mutations in the PKHD1 gene in two Iranian families with PKD. Materials and Methods: Genetic alterations of a 3-month-old boy and a 27-year-old girl with PKD were evaluated using whole-exome sequencing. The PCR direct sequencing was performed to analyse the co-segregation of the variants with the disease in the family. Finally, the molecular function of the identified novel mutations was evaluated by in silico study. Results: In the 3 month-old boy, a novel homozygous frameshift mutation was detected in the PKHD1 gene, which can cause PKD. Moreover, we identified three novel heterozygous missense mutations in ATIC, VPS13B, and TP53RK genes. In the 27-year-old woman, with two recurrent abortions history and two infant mortalities at early weeks due to metabolic and/or renal disease, we detected a novel missense mutation on PKHD1 gene and a novel mutation in ETFDH gene. Conclusion: In general, we have identified two novel mutations in the PKHD1 gene. These molecular findings can help accurately correlate genotype and phenotype in families with such disease in order to reduce patient births through preoperative genetic diagnosis or better management of disorders.

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