Activated phosphoinositide 3-kinase δ syndrome caused by PIK3CD mutations: Expanding the phenotype

Abstract

Abstract Background Germline heterozygous gain-of-function (GOF) mutations in the PIK3CD gene lead to a rare primary immunodeficiency disease also known as activated phosphoinositide 3-kinase (PI3K) δ syndrome type 1(APDS1). Affected patients present with recurrent infections, increased levels of serum IgM, lymphoproliferation, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia and the phenotypes are highly heterogeneous. We reported the clinical presentations and underlying genetic factors in three patients diagnosed with APDS1 from China. Methods Trio whole-exome sequencing (trio-WES) was performed in three patients with unclear diagnosis. Sanger sequencing and real-time quantitative PCR were used to confirm the variants identified. Results Two heterozygous mutations (c.3061G > A, p.E1021K and c.1574A > G, p.E525G) in PIK3CD (NM_005026.3) were identified by whole exome sequencing in the three patients. One of two patients with the mutation (c.3061G > A) presented with abdominal pain as the first symptom, which was due to intussusception caused by multiple polyps of colon. The patient with mutation (c.1574A > G) in had an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-like clinical manifestations, including multisystemic inflammation, acute glomerulonephritis, and positive perinuclear ANCA (p-ANCA), and microscopic polyangiitis (MPA), one of the subtypes of AAV, was considered. Conclusions We report some novel phenotype and genotype features of three patients with PIK3CD mutations. This is the first time to report PI3CKD-asociated intussusception and MPA. Our study suggested AAV-MPA may be novel phenotype of GOF mutations in this gene and our data expand the clinical spectrum of APDS. Trial registration: retrospectively registered.