scholarly journals Genetic Profile of Inborn Errors of Immunity Using Whole Exome Sequencing in Individuals With BCG Localized Adverse Events

2021 ◽  
Author(s):  
Sandra Aparecida Moreira Gomes Monteiro ◽  
Renan Paulo Martin ◽  
Rafael Filippelli-Silva ◽  
Maryana Mara Marins ◽  
Caio Perez Gomes ◽  
...  
Keyword(s):  
Adverse Events ◽  
Severe Form ◽  
Genetic Profile ◽  
Inborn Errors ◽  
Pathogenic Variants ◽  
Inborn Errors Of Immunity ◽  
Whole Exome ◽  
Immunity Genes ◽  
History Of ◽  
Clinical Conditions

Abstract Purpose: In Mycobacterium tuberculosis endemic regions, BCG vaccine is administered early after birth to confer protection against severe form of tuberculosis disease. Previous reports suggest that BCG adverse events, even localized ones (BCGitis), can be the first manifestation of immunodeficiency. We investigated children with a history of BCGitis who needed drug treatment looking for possibly pathogenic variants in inborn errors of immunity genes (IEI-genes). Methods: Forty-four probands were evaluated. The exome sequences obtained by Next-Generation Sequencing were filtered for variants in the 344 IEI-genes described by the International Union of Immunological Societies (IUIS) and classified according to the recommendations of the American College of Medical Genetics. The identified candidate variants were validated by Sanger sequencing. Results: Out of the 44 probands, 36 were sporadic cases and 8 were familial cases. Thirty-one in 44 (70.5%) presented immunoallergic or other infectious clinical conditions besides BCGitis; 19 in 44 (43.2%) presented variants classified as pathogenic or likely pathogenic in 17 different IEI-genes, of which 35.3% were genes related to defects in intrinsic and innate immunity, including Mendelian Susceptibility to Mycobacterial Disease (MSMD) genes (IRF8, IFNGR1, JAK1, STAT1, TLR3 and TBK1). Remaining genes were distributed in another five IUIS classifications groups (CARD14, CFH, CHD7, FOXN1, NFAT5, NLRP3, NOD2, PMS2, STAT3, TNFRSF13B and TNFSF12). Conclusion: The high prevalence of pathogenic or likely pathogenic variants found in IEI-genes may be associated with BCGitis, which should be considered a sign of an inborn error of immunity.

Whole-Exome Sequencing-Based Approach for Germline Mutations in Patients with Inborn Errors of Immunity

2020 ◽  
Vol 40 (5) ◽  
pp. 729-740 ◽  
Author(s):  
Tsubasa Okano ◽  
Kohsuke Imai ◽  
Takuya Naruto ◽  
Satoshi Okada ◽  
Motoi Yamashita ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Germline Mutations ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome

scholarly journals Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

2018 ◽  
Author(s):  
Brooke N. Wolford ◽  
Whitney E. Hornsby
Keyword(s):  
Family History ◽  
Aortic Dissection ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Family Members ◽  
Aortic Disease ◽  
Thoracic Aortic Dissection ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
History Of

ABSTRACTBackgroundThoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members.MethodsWe performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.ResultsTwenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed significant risk factors associated with pathogenic variants are age <50 [odds ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7).ConclusionsClinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset of aortic dissection <50 years old, family history of aortic disease, and no history of hypertension.

scholarly journals Novel Discoveries in Immune Dysregulation in Inborn Errors of Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Anwen Ren ◽  
Wei Yin ◽  
Heather Miller ◽  
Lisa S. Westerberg ◽  
Fabio Candotti ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Genome Sequencing ◽  
Immune Dysregulation ◽  
Genetic Mutation ◽  
Disease Monitoring ◽  
Whole Genome ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome

With the expansion of our knowledge on inborn errors of immunity (IEI), it gradually becomes clear that immune dysregulation plays an important part. In some cases, autoimmunity, hyperinflammation and lymphoproliferation are far more serious than infections. Thus, immune dysregulation has become significant in disease monitoring and treatment. In recent years, the wide application of whole-exome sequencing/whole-genome sequencing has tremendously promoted the discovery and further studies of new IEI. The number of discovered IEI is growing rapidly, followed by numerous studies of their pathogenesis and therapy. In this review, we focus on novel discovered primary immune dysregulation diseases, including deficiency of SLC7A7, CD122, DEF6, FERMT1, TGFB1, RIPK1, CD137, TET2 and SOCS1. We discuss their genetic mutation, symptoms and current therapeutic methods, and point out the gaps in this field.

scholarly journals Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hosneara Akter ◽  
Mohammad Shahnoor Hossain ◽  
Nushrat Jahan Dity ◽  
Md. Atikur Rahaman ◽  
K. M. Furkan Uddin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diseases ◽  
Leigh Syndrome ◽  
Genetic Profile ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Rare Genetic Diseases ◽  
Compound Heterozygous Variants

AbstractCollectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet–Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.

scholarly journals Whole-exome sequencing for detecting inborn errors of immunity: overview and perspectives

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2056
Author(s):  
Barbara Bosch ◽  
Yuval Itan ◽  
Isabelle Meyts
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Mechanisms ◽  
Future Research ◽  
Sequencing Analysis ◽  
Genetic Etiology ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome ◽  
Clinical Description

The study of inborn errors of immunity is based on a comprehensive clinical description of the patient’s phenotype and the elucidation of the underlying molecular mechanisms and their genetic etiology. Deciphering the pathogenesis is key to genetic counseling and the development of targeted therapy. This review shows the power of whole-exome sequencing in detecting inborn errors of immunity along five central steps taken in whole-exome sequencing analysis. In parallel, we highlight the challenges for the clinical and scientific use of the method and how these hurdles are currently being addressed. We end by ruminating on major areas in the field open to future research.

How I Treat: Allogeneic HSCT for adults with Inborn Errors of Immunity

Blood ◽  
2021 ◽  
Author(s):  
Siobhan Burns ◽  
Emma C Morris
Keyword(s):  
Patient Selection ◽  
Severe Disease ◽  
Severe Infection ◽  
Cell Transplant ◽  
Inherited Disorders ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Inborn Errors Of Immunity ◽  
Long Term Follow Up ◽  
History Of

Inborn Errors of Immunity (IEI) are rare inherited disorders arising from monogenic germline mutations in genes that regulate the immune system. The majority of IEI are Primary Immunodeficiencies characterised by severe infection often associated with autoimmunity, autoinflammation and/or malignancy. Allogeneic hematopoietic stem cell transplant (HSCT) has been the corrective treatment of choice for many IEI presenting with severe disease in early childhood and experience has made this a successful and comparatively safe treatment in affected children. Early HSCT outcomes in adults were poor, resulting in extremely limited use worldwide. This is changing due to a combination of improved IEI diagnosis to inform patient selection, better understanding of the natural history of specific IEI and improvements in transplant practice. Recently published HSCT outcomes for adults with IEI have been comparable with pediatric data, making HSCT an important option for correction of clinically severe IEI in adulthood. Here we discuss our practice for patient selection, timing of HSCT, donor selection and conditioning, peri- and post HSCT management and our approach to long term follow up. We stress the importance of multidisciplinary involvement in the complex decision-making process that we believe is required for successful outcomes in this rapidly emerging area.

scholarly journals Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes

2020 ◽  
Vol 29 (1) ◽  
pp. 88-98
Author(s):  
Elisabetta Di Fede ◽  
Valentina Massa ◽  
Bartolomeo Augello ◽  
Gabriella Squeo ◽  
Emanuela Scarano ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
De Novo ◽  
Clinical Signs ◽  
Pathogenic Variants ◽  
Mutational Screening ◽  
Whole Exome ◽  
Epigenetic Machinery ◽  
Custom Made ◽  
Clinical Conditions ◽  
Generation Sequencing

AbstractLysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as “writer” of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann–Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein–Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.

scholarly journals Whole exome sequencing in inborn errors of immunity

2017 ◽  
Vol 17 (6) ◽  
pp. 421-430 ◽  
Author(s):  
Giorgia Bucciol ◽  
Erika Van Nieuwenhove ◽  
Leen Moens ◽  
Yuval Itan ◽  
Isabelle Meyts
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome

scholarly journals Severe COVID-19 in Hospitalized Carriers of Single CFTR Pathogenic Variants

2021 ◽  
Vol 11 (6) ◽  
pp. 558
Author(s):  
Margherita Baldassarri ◽  
Francesca Fava ◽  
Chiara Fallerini ◽  
Sergio Daga ◽  
Elisa Benetti ◽  
...  
Keyword(s):  
Respiratory Tract Infections ◽  
Clinical Presentation ◽  
Severe Form ◽  
Multivariate Regression Model ◽  
Mechanically Ventilated ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Host Genetic ◽  
Tract Infections ◽  
Pandemic Wave

The clinical presentation of COVID-19 is extremely heterogeneous, ranging from asymptomatic to severely ill patients. Thus, host genetic factors may be involved in determining disease presentation and progression. Given that carriers of single cystic fibrosis (CF)-causing variants of the CFTR gene—CF-carriers—are more susceptible to respiratory tract infections, our aim was to determine their likelihood of undergoing severe COVID-19. We implemented a cohort study of 874 individuals diagnosed with COVID-19, during the first pandemic wave in Italy. Whole exome sequencing was performed and validated CF-causing variants were identified. Forty subjects (16 females and 24 males) were found to be CF-carriers. Among mechanically ventilated patients, CF-carriers were more represented (8.7%) and they were significantly (p < 0.05) younger (mean age 51 years) compared to noncarriers (mean age 61.42 years). Furthermore, in the whole cohort, the age of male CF-carriers was lower, compared to noncarriers (p < 0.05). CF-carriers had a relative risk of presenting an abnormal inflammatory response (CRP ≥ 20 mg/dL) of 1.69 (p < 0.05) and their hazard ratio of death at day 14 was 3.10 (p < 0.05) in a multivariate regression model, adjusted for age, sex and comorbidities. In conclusion, CF-carriers are more susceptible to the severe form of COVID-19, showing also higher risk of 14-day death.

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