Germline heterozygous gain-of-function (GOF) mutations in the PIK3CD gene lead to a rare primary immunodeficiency disease known as activated phosphoinositide 3-kinase (PI3K) δ syndrome type 1(APDS1). Affected patients present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation, increased levels of serum immunoglobulin (Ig) M, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia. Due to highly heterogeneous phenotypes of APDS1, it is very likely that suspected cases may be misdiagnosed. Herein we reported three patients with different clinical presentations but harboring pathogenic variants in PIK3CD gene detected by trio whole-exome sequencing (trio-WES) and confirmed by subsequent Sanger sequencing. Two heterozygous mutations (c.3061G > A, p.E1021K and c.1574 A > G, p.E525G) in PIK3CD (NM_005026.3) were identified by whole exome sequencing (WES) in the three patients. One of two patients with the mutation (c.3061G > A) presented with abdominal pain and diarrhea as the first symptoms, which was due to intussusception caused by multiple polyps of colon. The patient with mutation (c.1574 A > G) had an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-like clinical manifestations, including multisystemic inflammation, acute nephritic syndrome, and positive perinuclear ANCA (p-ANCA), thus the diagnosis of ANCA-AAV was considered. Our study expands the spectrums of clinical phenotype and genotype of APDS, and demonstrates that WES has a high molecular diagnostic yield for patients with immunodeficiency related symptoms, such as respiratory infections, multiple ecchymosis, ANCA-associated vasculitis, multiple ileocecal polyps, hepatosplenomegaly, and lymphoid hyperplasia. Retrospectively registered.

中文翻译：

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PIK3CD突变引起的活化磷酸肌醇3激酶δ综合征：扩大表型

PIK3CD 基因的种系杂合功能获得 (GOF) 突变会导致一种罕见的原发性免疫缺陷病，称为活化磷酸肌醇 3 激酶 (PI3K) δ 综合征 1 型 (APDS1)。受影响的患者呈现一系列临床表现，特别是反复呼吸道感染和淋巴细胞增殖、血清免疫球蛋白 (Ig) M 水平升高、EB 病毒 (EBV) 和巨细胞病毒 (CMV) 病毒血症。由于APDS1表型高度异质性，疑似病例很可能被误诊。在此，我们报告了三名具有不同临床表现但携带 PIK3CD 基因致病性变异的患者，通过三重全外显子组测序 (trio-WES) 检测到，并通过随后的桑格测序证实。通过全外显子组测序 (WES) 在三名患者中鉴定出 PIK3CD (NM_005026.3) 中的两个杂合突变 (c.3061G > A、p.E1021K 和 c.1574 A > G、p.E525G)。两名携带该突变（c.3061G > A）的患者中，有一名以腹痛和腹泻为首发症状，这是由于多发性结肠息肉引起的肠套叠所致。突变（c.1574 A > G）患者具有抗中性粒细胞胞浆抗体（ANCA）相关血管炎（AAV）样临床表现，包括多系统炎症、急性肾炎综合征和核周ANCA（p-ANCA）阳性，因此考虑ANCA-AAV的诊断。我们的研究扩展了 APDS 的临床表型和基因型范围，并证明 WES 对患有免疫缺陷相关症状的患者具有较高的分子诊断率，例如呼吸道感染、多发性瘀斑、ANCA 相关血管炎、多发性回盲部息肉、肝脾肿大和淋巴组织增生。已追溯登记。