Homozygous duplication identified by whole genome sequencing causes LRBA deficiency.

Journal

NPJ genomic medicine
ISSN: 2056-7944
Titre abrégé: NPJ Genom Med
Pays: England
ID NLM: 101685193

Informations de publication

Date de publication:
18 Nov 2021
Historique:
received: 04 01 2021
accepted: 21 10 2021
entrez: 19 11 2021
pubmed: 20 11 2021
medline: 20 11 2021
Statut: epublish

Résumé

In more than one-third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole-exome sequencing (WES) fails to identify the genetic defect. Whole-genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation, and hypogammaglobulinemia, typical of lipopolysaccharide-responsive and beige-like anchor (LRBA) or cytotoxic T lymphocyte antigen 4 (CTLA4) deficiencies. Gene-panel sequencing, comparative genomic hybridization (CGH) array, and WES failed to reveal a genetic aberration in relevant genes. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene. The variant was validated by PCR and Sanger sequencing, demonstrating the presence of the junction between the reference and the tandem-duplicated sequence. Droplet digital PCR (ddPCR) further confirmed the copy number in the unaffected parents (CN = 3, heterozygous) and affected siblings (CN = 4, homozygous), confirming the expected segregation pattern. In cases of suspected inherited immunodeficiency, WGS may reveal a mutation when other methods such as microarray and WES analysis failed to detect an aberration.

Identifiants

DOI: 10.1038/s41525-021-00263-z PMID: 34795304 PMC: PMC8602677
pubmed: 34795304
doi: 10.1038/s41525-021-00263-z
pii: 10.1038/s41525-021-00263-z
pmc: PMC8602677
doi:

Types de publication

Journal Article

Langues

eng

Pagination

96

Subventions

Organisme : Qatar National Research Fund (QNRF)
ID : PPM1-1229-15002
Organisme : Qatar National Research Fund (QNRF)
ID : NPRP10-0202-170320
Organisme : Qatar National Research Fund (QNRF)
ID : PPM1-1229-15002
Organisme : Qatar National Research Fund (QNRF)
ID : NPRP10-0202-170320

Informations de copyright

© 2021. The Author(s).

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Auteurs

Daniele Merico (D)

The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, M5G 0A4, ON, Canada.
Deep Genomics Inc., Toronto, M5G 1M1, ON, Canada.
ORCID: 0000-0002-3728-4401

Yehonatan Pasternak (Y)

Canadian Center for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, Toronto, M5G1X8, ON, Canada.
Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, M5G 1×8, ON, Canada.
University of Toronto, Toronto, M5S 1A8, ON, Canada.

Mehdi Zarrei (M)

The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, M5G 0A4, ON, Canada.

Edward J Higginbotham (EJ)

The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, M5G 0A4, ON, Canada.
ORCID: 0000-0003-1881-9308

Bhooma Thiruvahindrapuram (B)

The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, M5G 0A4, ON, Canada.

Ori Scott (O)

Canadian Center for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, Toronto, M5G1X8, ON, Canada.
Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, M5G 1×8, ON, Canada.
University of Toronto, Toronto, M5S 1A8, ON, Canada.
ORCID: 0000-0002-3470-5725

Jessica Willett-Pachul (J)

Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, M5G 1×8, ON, Canada.

Eyal Grunebaum (E)

Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, M5G 1×8, ON, Canada.
University of Toronto, Toronto, M5S 1A8, ON, Canada.

Julia Upton (J)

Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, M5G 1×8, ON, Canada.
University of Toronto, Toronto, M5S 1A8, ON, Canada.

Adelle Atkinson (A)

Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, M5G 1×8, ON, Canada.
University of Toronto, Toronto, M5S 1A8, ON, Canada.

Vy H D Kim (VHD)

Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, M5G 1×8, ON, Canada.
University of Toronto, Toronto, M5S 1A8, ON, Canada.

Elbay Aliyev (E)

Department of Human Genetics, Sidra Medicine, Doha, Qatar.
ORCID: 0000-0002-6469-1854

Khalid Fakhro (K)

Department of Human Genetics, Sidra Medicine, Doha, Qatar.
Department of Genetic Medicine, Weill-Cornell Medical College, Doha, Qatar.
ORCID: 0000-0002-3150-1276

Stephen W Scherer (SW)

The Centre for Applied Genomics (TCAG), Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, M5G 0A4, ON, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, ON, Canada.
McLaughlin Centre, University of Toronto, Toronto, M5G 0A4, ON, Canada.
ORCID: 0000-0002-8326-1999

Chaim M Roifman (CM)

Canadian Center for Primary Immunodeficiency and the Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, Toronto, M5G1X8, ON, Canada. chaim.roifman@sickkids.ca.
Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, M5G 1×8, ON, Canada. chaim.roifman@sickkids.ca.
University of Toronto, Toronto, M5S 1A8, ON, Canada. chaim.roifman@sickkids.ca.
ORCID: 0000-0002-7519-4116

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