Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies

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Abstract

Background

Systemic lupus erythematosus (SLE) comprise a diverse range of clinical manifestations. To date, more than 30 single gene causes of lupus/lupus like syndromes in humans have been identified. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to phenotypic and genetic heterogeneity.

Methods

We employed whole exome sequencing (WES) in patients presenting with childhood-onset lupus with severe and/or atypical presentations to identify cases that are explained by a single-gene (monogenic) cause.

Results

From January 2015 to June 2018 15 new cases of childhood-onset SLE were diagnosed in Edmond and Lily Safra Children’s Hospital. By WES we identified causative mutations in four subjects in five different genes: C1QC, SLC7A7, MAN2B1, PTEN and STAT1. No molecular diagnoses were established on clinical grounds prior to genetic testing.

Conclusions

We identified a significant fraction of monogenic SLE etiologies using WES and confirm the genetic locus heterogeneity in childhood-onset lupus. These results highlight the importance of establishing a genetic diagnosis for children with severe or atypical lupus by providing accurate and early etiology-based diagnoses and improving subsequent clinical management.

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Most cited references 65

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Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.

Jennifer E. Posey, Tamar Harel, Pengfei Liu … (2017)

Background Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes. Methods We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology. Results A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77×10(-7)). Conclusions In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).

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Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.

M Botto, C Dell'Agnola, A E Bygrave … (1998)

The complement system plays a paradoxical role in the development and expression of autoimmunity in humans. The activation of complement in systemic lupus erythematosus (SLE) contributes to tissue injury. In contrast, inherited deficiency of classical pathway components, particularly C1q (ref. 1), is powerfully associated with the development of SLE. This leads to the hypothesis that a physiological action of the early part of the classical pathway protects against the development of SLE (ref. 2) and implies that C1q may play a key role in this respect. C1q-deficient (C1qa-/-) mice were generated by gene targeting and monitored for eight months. C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.

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STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis.

Frank van de Veerdonk, Theo Plantinga, Alexander Hoischen … (2011)

Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to candida infection of skin, nails, and mucous membranes. Patients with recessive CMC and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of autosomal dominant CMC is unknown. We evaluated 14 patients from five families with autosomal dominant CMC. We incubated their peripheral-blood mononuclear cells with different combinations of stimuli to test the integrity of pathways that mediate immunity, which led to the selection of 100 genes that were most likely to contain the genetic defect. We used an array-based sequence-capture assay, followed by next-generation sequencing, to identify mutations. The mononuclear cells from the affected patients were characterized by poor production of interferon-γ, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. We identified heterozygous missense mutations in the DNA sequence encoding the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) in the patients. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17). The interferon-γ receptor pathway was intact in these patients. Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection. (Funded by the Netherlands Organization for Scientific Research and others.).

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Author and article information

Contributors

Irit Tirosh: irit.tirosh@sheba.health.gov.il

Shiri Spielman: shiri.spielman@sheba.health.gov.il

Ortal Barel: ortal.barel@sheba.health.gov.il

Reut Ram: reut.ram@sheba.health.gov.il

Tali Stauber: tali.stauber@sheba.health.gov.il

Gideon Paret: gidi.paret@sheba.health.gov.il

Marina Rubinsthein: marina.rubinshtein@sheba.health.gov.il

Itai M. Pessach: itai.pessach@sheba.health.gov.il

Maya Gerstein: maya.gerstein@sheba.health.gov.il

Yair Anikster: yair.anikster@sheba.health.gov.il

Rachel Shukrun: shukrun.rachel@gmail.com

Adi Dagan: adi.dagan@sheba.health.gov.il

Katerina Adler: katerina.adler@sheba.health.gov.il

Ben Pode-Shakked: ben.podeshakhed@sheba.health.gov.il

Alexander Volkov: alexander.volkov@sheba.health.gov.il

Marina Perelman: marina.perelman@sheba.health.gov.il

Shoshana Greenberger: shoshana.greenberger@sheba.health.gov.il

Raz Somech: raz.somech@sheba.health.gov.il

Einat Lahav: einat.azaria@sheba.health.gov.il

Amar J. Majmundar: amar.majmundar@childrens.harvard.edu

Shai Padeh: shaypa@mac.com

Friedhelm Hildebrandt: friedhelm.hildebrandt@childrens.harvard.edu

Asaf Vivante: asaf.vivante@sheba.health.gov.il , asafvivante@gmail.com

Journal

Journal ID (nlm-ta): Pediatr Rheumatol Online J

Journal ID (iso-abbrev): Pediatr Rheumatol Online J

Title: Pediatric Rheumatology Online Journal

Publisher: BioMed Central (London )

ISSN (Electronic): 1546-0096

Publication date (Electronic): 30 July 2019

Publication date PMC-release: 30 July 2019

Publication date Collection: 2019

Volume: 17

Electronic Location Identifier: 52

Affiliations

[1 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Department of Pediatrics B, Edmond and Lily Safra Children’s Hospital, Sackler Faculty of Medicine, , Sheba Medical Center, ; Tel-Hashomer, 5265601 Ramat Gan, Israel

[2 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Rheumatology Unit, Edmond and Lily Safra Children’s Hospital, , Sheba Medical Center, ; Tel-Hashomer, Israel

[3 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Department of Pediatrics A Edmond and Lily Safra Children’s Hospital, , Sheba Medical Center, ; Tel-Hashomer, Israel

[4 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Intensive care unit, Edmond and Lily Safra Children’s Hospital, , Sheba Medical Center, ; Tel-Hashomer, Israel

[5 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Metabolic Disease Unit, Edmond and Lily Safra Children’s Hospital, , Sheba Medical Center, ; Tel-Hashomer, Israel

[6 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Pathology Department, , Sheba Medical Center, ; Tel-Hashomer, Israel

[7 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Department of Dermatology, , Sheba Medical Center, ; Tel-Hashomer, Israel

[8 ]ISNI 0000 0004 1937 0546, GRID grid.12136.37, Sackler Faculty of Medicine, , Tel-Aviv University, ; Tel-Aviv, Israel

[9 ]ISNI 000000041936754X, GRID grid.38142.3c, Division of Nephrology, Department of Medicine, Boston Children’s Hospital, , Harvard Medical School, ; Boston, MA USA

[10 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, The Genomic Unit, Sheba Cancer Research Center, , Sheba Medical Center, ; Tel Hashomer, Israel

[11 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Nephrology Unit, Edmond and Lily Safra Children’s Hospital, Sackler Faculty of Medicine, Sheba Medical Center, Tel Hashomer, ; 5265601 Ramat Gan, Israel

Article

Publisher ID: 349

DOI: 10.1186/s12969-019-0349-y

PMC ID: 6668194

PubMed ID: 31362757

SO-VID: 8a266f30-1d4a-419c-a309-de95d81cb5e8

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 June 2019

Date accepted : 8 July 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;

Award ID: DK-076683-13

Award ID: T32DK-007726

Award Recipient : Amar J. Majmundar Friedhelm Hildebrandt

Custom metadata

ScienceOpen disciplines: Pediatrics

Keywords: wes,sle,monogenic

Data availability:

ScienceOpen disciplines: Pediatrics

Keywords: wes, sle, monogenic

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Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies

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Abstract

Background

Methods

Results

Conclusions

Related collections

Estudio del peso al nacer

Most cited references 65

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.

Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.

STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis.

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Cited by 20

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