DOI: 10.1101/499988Dec 21, 2018Paper

Whole Genome Sequencing of Primary Immunodeficiency reveals a role for common and rare variants in coding and non-coding sequences

BioRxiv : the Preprint Server for Biology
James E ThaventhiranKenneth G C Smith


Primary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of 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 malignancies. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 subjects. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 8.2%, while a Bayesian approach (BeviMed1) identified multiple potential new disease-associated genes. Exploration of the non-coding space revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified novel PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance m...Continue Reading

Related Concepts

Autoimmune Diseases
Malignant Neoplasms
Gene Deletion
Gene Therapy
Immune Response
Primary Immune Deficiency Disorder

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