CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease

Abstract Background Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. Methods To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. Results Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. Conclusion Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

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Novel TNFAIP3 microdeletion in a girl with infantile-onset inflammatory bowel disease complicated by a severe perianal lesion

Human Genome Variation ◽

10.1038/s41439-020-00128-4 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Kosuke Taniguchi ◽

Mikihiro Inoue ◽

Katsuhiro Arai ◽

Keiichi Uchida ◽

Osuke Migita ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Bowel Disease ◽

Early Onset ◽

De Novo ◽

Loss Of Function ◽

Whole Exome ◽

Inflammatory Bowel

AbstractA20 haploinsufficiency (HA20), a disease caused by loss-of-function TNFAIP3 mutations, manifests various autoinflammatory and/or autoimmune symptoms. Some cases of HA20 were initially diagnosed as very early onset inflammatory bowel disease (VEO-IBD). We performed whole-exome sequencing (WES) for a Japanese girl with infantile-onset IBD and a severe perianal lesion and detected a novel de novo 119 kb microdeletion containing only TNFAIP3 (arr[GRCh37] 6q23.3(138125829_138244816) × 1).

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718 Whole Exome Sequencing in Cohort of Very Early Onset Inflammatory Bowel Disease

Gastroenterology ◽

10.1016/s0016-5085(14)60450-9 ◽

2014 ◽

Vol 146 (5) ◽

pp. S-125

Author(s):

Christopher J. Moran ◽

Judith R. Kelsen ◽

Jess L. Kaplan ◽

Mariah Baril-Dore ◽

Elizabeth Petit ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Bowel Disease ◽

Early Onset ◽

Whole Exome ◽

Inflammatory Bowel

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Whole-exome sequencing of DNA from peripheral blood mononuclear cells (PBMC) and EBV-transformed lymphocytes from the same donor

BMC Genomics ◽

10.1186/1471-2164-12-464 ◽

2011 ◽

Vol 12 (1) ◽

Cited By ~ 29

Author(s):

Eric R Londin ◽

Margaret A Keller ◽

Michael R D'Andrea ◽

Kathleen Delgrosso ◽

Adam Ertel ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Whole Exome ◽

Blood Mononuclear Cells

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Single-cell multi-omics analysis of the immune response in COVID-19

Nature Medicine ◽

10.1038/s41591-021-01329-2 ◽

2021 ◽

Author(s):

Emily Stephenson ◽

◽

Gary Reynolds ◽

Rachel A. Botting ◽

Fernando J. Calero-Nieto ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Single Cell ◽

Mononuclear Cells ◽

Severe Disease ◽

Effector Memory ◽

Peripheral Blood Mononuclear ◽

Cross Sectional ◽

Hematopoietic Stem ◽

Symptomatic Disease

AbstractAnalysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

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UTILIZATION OF WHOLE EXOME SEQUENCING DATA TO IDENTIFY CLINICALLY RELEVANT PHARMACOGENOMIC VARIANTS IN INFLAMMATORY BOWEL DISEASE

Gastroenterology ◽

10.1053/j.gastro.2021.01.119 ◽

2021 ◽

Vol 160 (3) ◽

pp. S43

Author(s):

Daniel Mulder ◽

Sam Khalouei ◽

Neil Warner ◽

Claudia Gonzaga-Jauregui ◽

Peter Church ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Bowel Disease ◽

Sequencing Data ◽

Exome Sequencing Data ◽

Whole Exome ◽

Whole Exome Sequencing Data ◽

Inflammatory Bowel

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PCNT point mutations and familial intracranial aneurysms

Neurology ◽

10.1212/wnl.0000000000006614 ◽

2018 ◽

Vol 91 (23) ◽

pp. e2170-e2181 ◽

Cited By ~ 6

Author(s):

Oswaldo Lorenzo-Betancor ◽

Patrick R. Blackburn ◽

Emily Edwards ◽

Rocío Vázquez-do-Campo ◽

Eric W. Klee ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Intracranial Aneurysms ◽

Point Mutations ◽

Missense Mutations ◽

Loss Of Function ◽

Interaction Domain ◽

Knockout Mouse Model ◽

Whole Exome ◽

Primordial Dwarfism

ObjectiveTo identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing.MethodsWe performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants.ResultsWe identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases.ConclusionThe PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt−/−) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.

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Identification of a Novel EXT Mutation in A Kindred With Hereditary Multiple Exostoses Using Whole-Exome Sequencing and Overview of Mutation Spectrum

10.21203/rs.3.rs-770260/v1 ◽

2021 ◽

Author(s):

yanhan deng ◽

yujian liu ◽

wei tu ◽

liu yang

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Mutation Spectrum ◽

Loss Of Function ◽

Site Mutation ◽

Hereditary Multiple Exostoses ◽

Multiple Osteochondromas ◽

Online Databases ◽

Whole Exome ◽

Multiple Exostoses

Abstract Background: Hereditary Multiple Osteochondromas(HMO) is a rare genetic musculoskeletal disorder characterized by multiple osteochondromas that form near to the growth plates of many bones. Loss-of-function mutations in EXT1 or EXT2 that encode glycosyltrasferases are the causal mutations for most HMO patients.Methods: After collecting the family history and clinical information, we used Whole-Exome Sequencing to find the pathogenic mutations in one Chinese Hereditary Multiple Exostoses pedigree. Sanger sequencing and relevant online databases were used to validate the screened variants. Lollipop plots were drew to map the reported mutations from online databases (Multiple Osteochondroma Mutation Database and clinvar)on a linear protein domains by MutationMapper.Results: A novel heterozygous splicing-site mutation in gene EXT1 (NM_000127:exon5:c.1417+1G>C，chr8:118834703) was found in this pedigree and mutation spectrum of genes EXT1 and EXT2 were demonstrated.Conclusions: Our results help this pedigree to identify the pathogenic variant and guide the prenatal diagnosis, also expand the mutation spectrum in Hereditary Multiple Osteochondromas.

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Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

10.1101/2020.03.15.993113 ◽

2020 ◽

Author(s):

Chih-Fen Hu ◽

G. W. Gant Luxton ◽

Feng-Chin Lee ◽

Chih-Sin Hsu ◽

Shih-Ming Huang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Modifiers ◽

Loss Of Function ◽

Dyt1 Dystonia ◽

Whole Exome ◽

Important Regulator ◽

Blood Leukocyte ◽

Aaa Protein ◽

Neurological Movement Disorder

AbstractBackgroundDYT1 dystonia is a neurological movement disorder characterized by painful sustained muscle contractions resulting in abnormal twisting and postures. In a subset of patients, it is caused by a loss-of-function mutation (ΔE302/303; or ΔE) in the luminal ATPases associated with various cellular activities (AAA+) protein torsinA encoded by the TOR1A gene. The low penetrance of the ΔE mutation (∼30-40%) suggests the existence of unknown genetic modifiers of DYT1 dystonia.MethodsTo identify these modifiers, we performed whole exome sequencing of blood leukocyte DNA isolated from two DYT1 dystonia patients, three asymptomatic carriers of the ΔE mutation, and an unaffected adult relative.ResultsA total of 264 DYT1 dystonia-associated variants (DYT1 variants) were identified in 195 genes. Consistent with the emerging view of torsinA as an important regulator of the cytoskeleton, endoplasmic reticulum homeostasis, and lipid metabolism, we found DYT1 variants in genes that encode proteins implicated in these processes. Moreover, 40 DYT1 variants were detected in 32 genes associated with neuromuscular and neuropsychiatric disorders.ConclusionThe DYT1 variants described in this work represent exciting new targets for future studies designed to increase our understanding of the pathophysiology and pathogenesis of DYT1 dystonia.

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