Why are you hitting yourself? Whole-exome sequencing diagnosis of monogenic autoimmunity

Abstract

Introduction: Self-tolerance and regulation are fundamental functions of the immune system. Inborn errors of immunity (IEI) have broad clinical manifestations and autoimmune diseases are frequently encountered. Objective: We aimed to identify monogenic etiologies in our patients with early-onset, familial presentation, multiple autoimmune diseases (AID), or autoimmunity associated with other features. MethodsPatients were diagnosed with AID by their clinicians based on currently accepted international criteria. They were deemed high-priority for whole-exome sequencing (WES) if they had a close family history of autoimmune diseases, early-onset, polyautoimmunity, or other characteristics associated with their autoimmune phenotype. Results: Twenty-six patients with AID were included over three years. Most patients were female (69%) and the median age at onset was 5.5 years. Onefifth of the patients (19%) had a history of inbreeding and 23% had a close relative with autoimmunity. The most frequently encountered phenotypes were Systemic Lupus Erythematosus (SLE) or SLE-like diseases (50%), vasculitis (27%), and autoimmune cytopenias (23%). Over half of the patients had multiple autoimmune disorders. Other common features included viral (50%), bacterial (42%), and fungal (27%) susceptibility. WES yielded a diagnosis compatible with the phenotype in over half of the patients: ADAR, DNASE13L, RIPK1, CASP10, C1QA, CFI, TPP2, STAT3-GOF, STAT5B-GOF, NLRC4-GOF, SAMD9-GOF, SAMD9L, RNF213, LMNA. Potential gene candidates were identified in 42% (MEFV, DR6, IFNL3, THBS1, HMGB2) and the genetic dx was undetermined in 4%. DiscussionIn recent years more IEI have been described, and more autoimmune phenotypes are being identified. In patients with early-onset, family history, or polyautoimmunity, WES can be diagnostic in over half of the patients. The treatment of patients with coexisting immune dysregulation and deficiency can be particularly challenging. A specific genetic diagnosis can help understand the underlying physiology in autoimmune disease and help tailor directed therapies; a new age of precision medicine in immunology is upon us. ConclusionThe increasing accessibility of genetic diagnosis can identify monogenic defects in a high proportion of patients with autoimmune diseases who present with early-onset, familiar cases, polyautoimmunity, or infection susceptibility associated with their autoimmune phenotype.