A maternal GOT1 novel variant associated with early-onset severe preeclampsia identified by whole-exome sequencing

Objective.Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder. Early-onset, familial, and/or syndromic SLE may reveal monogenic pathologies. The aim of this study was to examine genetic associations in patients with early-onset or familial SLE.Methods.We enrolled 7 SLE cases (from different families) with disease onset ≤ 5 years of age and family history consistent with an autosomal recessive inheritance. Whole exome sequencing (WES) was performed in 6 index cases. Suspected variants were confirmed by Sanger sequencing. We did not perform WES in 1 patient who had features similar to the first 3 cases; only the exons of C1QA, C1QB, and C1QC were screened with Sanger sequencing.Results.We demonstrated 2 novel and 3 previously reported variants in genes associated with SLE: a homozygous non-sense alteration (c.622C>T/p.Gln208Ter) in C1QA in 2 patients; homozygous non-sense alteration (c.79C>T/p.Gln27Ter) in C1QC in 1 (novel variant); homozygous missense alteration (c.100G>A/p.Gly34Arg) in C1QC in 1; homozygous missense alteration (c.1945G>C/p.Ala649Pro) in C1S in 1 (novel variant); and homozygous frameshift alteration (c.289_290delAC/p.Thr97Ilefs*2) in DNASE1L3 in 1 patient. Further, in 1 patient, we determined a strong candidate variant in HDAC7 (histone decetylase 7).Conclusion.Five patients had homozygous alterations in genes coding early complement proteins. This may lead to decreased clearance of apoptotic bodies. One patient had DNASE1L3 variant, which functions in the clearance of self-antigens. In 1 patient, we determined a novel gene that may be important in SLE pathogenesis. We suggest that monogenic causes/associations should be sought in early-onset and/or familial SLE.

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Integrated Protein Network Analysis of Whole Exome Sequencing Study of Severe Preeclampsia

10.1101/2020.11.23.20236885 ◽

2020 ◽

Author(s):

Jessica Schuster ◽

George A. Tollefson ◽

Valeria Zarate ◽

Anthony Agudelo ◽

Joan Stabila ◽

...

Keyword(s):

Network Analysis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Severe Preeclampsia ◽

Risk Scores ◽

Whole Exome ◽

Cluster A ◽

Shared Networks ◽

Unique Genes

AbstractTo identify clusters of patients with shared networks of genes associated with early onset severe preeclampsia from whole exome sequencing data through novel bioinformatic analysis.We performed a case-control study using whole exome sequencing (WES) on early onset preeclamptic mothers with severe features delivering < 34 weeks and mothers who delivered ≥ 37 weeks. Genotype testing identified variants that were differentially abundant between cases and controls. A Protein-Protein interaction (PPI) analysis and visualization tool, Proteinarium, was implemented to identify clusters of patients with shared networks associated with severe preeclampsia.A total of 61 early onset preeclamptic women with severe features and 82 race and ethnicity matched control women at term were sequenced. We identified 8,867 predicted deleterious variants. 21 of these variants were nominally associated with preeclampsia by genotype testing. Using Proteinarium129 out of the 143 sequenced patients were assigned to statistically significant clusters, Cluster A and B (p< 0.0001). Case dominated Cluster A contained 47 of the 61 case subjects. There were 13 unique genes in the PPI network of Cluster A compared to control dominated Cluster B. Amongst these unique genes, LAMB2, PTK2, RAC1, QSOX1, FN1, and VCAM1 have known associations with the pathogenic mechanisms of preeclampsia.Our network analysis identified genes that were unique to a large cluster of patients with shared networks that provide insights for severe preeclampsia. We also identified genes imputed from the interactome that may otherwise have not been identified by conventional analysis. Strict phenotyping of both cases and controls improved the likelihood of identifying these otherwise difficult to find genetic associations. These uniquely identified genes and their associated variants are potential candidates for developing polygenic risk scores for severe preeclampsia. These results support our hypothesis on the genetic architecture of complex diseases and are generalizable to other phenotypes.

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Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

European Journal of Human Genetics ◽

10.1038/ejhg.2015.173 ◽

2015 ◽

Vol 24 (5) ◽

pp. 710-716 ◽

Cited By ~ 42

Author(s):

Gaël Nicolas ◽

David Wallon ◽

Camille Charbonnier ◽

Olivier Quenez ◽

Stéphane Rousseau ◽

...

Keyword(s):

Alzheimer Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Whole Exome

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Early Onset Multiple Primary Tumors in Atypical Presentation of Cowden Syndrome Identified by Whole-Exome-Sequencing

Frontiers in Genetics ◽

10.3389/fgene.2018.00353 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 7

Author(s):

Mathias Cavaillé ◽

Flora Ponelle-Chachuat ◽

Nancy Uhrhammer ◽

Sandrine Viala ◽

Mathilde Gay-Bellile ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Cowden Syndrome ◽

Atypical Presentation ◽

Primary Tumors ◽

Multiple Primary Tumors ◽

Whole Exome ◽

Multiple Primary

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CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz103 ◽

2019 ◽

Vol 25 (11) ◽

pp. 1788-1795 ◽

Cited By ~ 8

Author(s):

Thomas Magg ◽

Anna Shcherbina ◽

Duran Arslan ◽

Mukesh M Desai ◽

Sarah Wall ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Mononuclear Cells ◽

Severe Disease ◽

Effector Memory ◽

Loss Of Function ◽

Peripheral Blood Mononuclear ◽

Whole Exome ◽

Inflammatory Bowel

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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