Dataset Information

Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

ABSTRACT: Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.

SUBMITTER: Thaventhiran JED

PROVIDER: S-EPMC7334047 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Thaventhiran James E D JED Lango Allen Hana H Burren Oliver S OS Rae William W Greene Daniel D Staples Emily E Zhang Zinan Z Farmery James H R JHR Simeoni Ilenia I Rivers Elizabeth E Maimaris Jesmeen J Penkett Christopher J CJ Stephens Jonathan J Deevi Sri V V SVV Sanchis-Juan Alba A Gleadall Nicholas S NS Thomas Moira J MJ Sargur Ravishankar B RB Gordins Pavels P Baxendale Helen E HE Brown Matthew M Tuijnenburg Paul P Worth Austen A Hanson Steven S Linger Rachel J RJ Buckland Matthew S MS Rayner-Matthews Paula J PJ Gilmour Kimberly C KC Samarghitean Crina C Seneviratne Suranjith L SL Sansom David M DM Lynch Andy G AG Megy Karyn K Ellinghaus Eva E Ellinghaus David D Jorgensen Silje F SF Karlsen Tom H TH Stirrups Kathleen E KE Cutler Antony J AJ Kumararatne Dinakantha S DS Chandra Anita A Edgar J David M JDM Herwadkar Archana A Cooper Nichola N Grigoriadou Sofia S Huissoon Aarnoud P AP Goddard Sarah S Jolles Stephen S Schuetz Catharina C Boschann Felix F Lyons Paul A PA Hurles Matthew E ME Savic Sinisa S Burns Siobhan O SO Kuijpers Taco W TW Turro Ernest E Ouwehand Willem H WH Thrasher Adrian J AJ Smith Kenneth G C KGC

Nature 20200506 7814

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lympho ...[more]

PMID: 32499645

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Project description:BackgroundIt is estimated that 1-13% of cases of bronchiectasis in adults globally are attributable to primary ciliary dyskinesia (PCD) but many adult patients with bronchiectasis have not been investigated for PCD. PCD is a disorder caused by mutations in genes required for motile cilium structure or function, resulting in impaired mucociliary clearance. Symptoms appear in infancy but diagnosis is often late or missed, often due to the lack of a "gold standard" diagnostic tool and non-specific symptoms. Mutations in > 50 genes account for around 70% of cases, with additional genes, and non-coding, synonymous, missense changes or structural variants (SVs) in known genes presumed to account for the missing heritability.MethodsUK patients with no identified genetic confirmation for the cause of their PCD or bronchiectasis were eligible for whole genome sequencing (WGS) in the Genomics England Ltd 100,000 Genomes Project. 21 PCD probands and 52 non-cystic fibrosis (CF) bronchiectasis probands were recruited in Wessex Genome Medicine Centre (GMC). We carried out analysis of single nucleotide variants (SNVs) and SVs in all families recruited in Wessex GMC.Results16/21 probands in the PCD cohort received confirmed (n = 9), probable (n = 4) or possible (n = 3) diagnosis from WGS, although 13/16 of these could have been picked up by current standard of care gene panel testing. In the other cases, SVs were identified which were missed by panel testing. We identified variants in novel PCD candidate genes (IFT140 and PLK4) in 2 probands in the PCD cohort. 3/52 probands in the non-CF bronchiectasis cohort received a confirmed (n = 2) or possible (n = 1) diagnosis of PCD. We identified variants in novel PCD candidate genes (CFAP53 and CEP164) in 2 further probands in the non-CF bronchiectasis cohort.ConclusionsGenetic testing is an important component of diagnosing PCD, especially in cases of atypical disease history. WGS is effective in cases where prior gene panel testing has found no variants or only heterozygous variants. In these cases it may detect SVs and is a powerful tool for novel gene discovery.

Dataset Information

Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Publications

Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

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