自身免疫性淋巴组织增生综合征 (ALPS) 是一种罕见的遗传性疾病，其特征为慢性淋巴结肿大、脾肿大、血细胞减少和淋巴瘤风险增加。将 ALPS 与具有重叠症状的免疫缺陷区分开来具有挑战性。本研究评估了辛辛那提儿童医院医疗中心针对 ALPS 的 15 基因 NGS 检测组的性能和诊断率。 2014 年 5 月至 2023 年 1 月期间，对提交给 ALPS NGS 小组的 802 名患者的样本进行了研究。共有 62 名患者 (7.7%) 得到明确诊断：52/62 例 (84%) 显示 37 种独特的致病性/可能致病性种系 FAS 变异支持 ALPS 诊断 (6.5%, 52/802)。另外满足异常 ALPS 免疫学结果标准的患者的 ALPS 诊断率增加至 30%。 17/37 (46%) 诊断性 FAS 变异是 ALPS 中首次报告的新变异。 10/802例（1.2%）显示与自身免疫性淋巴增殖性免疫缺陷（ALPID）相关的五个基因（ADA2、CTLA4、KRAS、MAGT1、NRAS）的诊断结果。家庭研究能够对意义不明的变异（VUS）进行重新分类，并识别FAS阳性患者的高危家庭成员，这有助于后续诊断和治疗。除了家族研究之外，完整的临床表型、异常的 ALPS 免疫学和 Fas 介导的细胞凋亡结果有助于澄清不确定的遗传发现。这项研究描述了北美最大的疑似 ALPS 基因检测队列，并强调了 ALPS NGS 组合在区分 ALPS 和非 ALPS 免疫缺陷方面的有效性。在权衡不同基因检测选项的成本、完整性和及时性后，可以考虑对未定义的 ALPS-U 患者或非 ALPS 免疫缺陷进行更全面的外显子组或基因组测序评估。© 2024。作者。

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder featuring chronic lymphadenopathy, splenomegaly, cytopenias, and increased lymphoma risk. Differentiating ALPS from immunodeficiencies with overlapping symptoms is challenging. This study evaluated the performance and the diagnostic yield of a 15-gene NGS panel for ALPS at Cincinnati Children's Hospital Medical Center. Samples from 802 patients submitted for ALPS NGS panel were studied between May 2014 and January 2023. A total of 62 patients (7.7%) had a definite diagnosis: 52/62 cases (84%) showed 37 unique pathogenic/likely pathogenic germline FAS variants supporting ALPS diagnosis (6.5%, 52/802). The ALPS diagnostic yield increased to 30% in patients who additionally fulfilled abnormal ALPS immunology findings criteria. 17/37 (46%) diagnostic FAS variants were novel variants reported for the first time in ALPS. 10/802 cases (1.2%) showed diagnostic findings in five genes (ADA2, CTLA4, KRAS, MAGT1, NRAS) which are related to autoimmune lymphoproliferative immunodeficiency (ALPID). Family studies enabled the reclassification of variants of unknown significance (VUS) and also the identification of at-risk family members of FAS-positive patients, which helped in the follow-up diagnosis and treatment. Alongside family studies, complete clinical phenotypes and abnormal ALPS immunology and Fas-mediated apoptosis results helped clarify uncertain genetic findings. This study describes the largest cohort of genetic testing for suspected ALPS in North America and highlights the effectiveness of the ALPS NGS panel in distinguishing ALPS from non-ALPS immunodeficiencies. More comprehensive assessment from exome or genome sequencing could be considered for undefined ALPS-U patients or non-ALPS immunodeficiencies after weighing cost, completeness, and timeliness of different genetic testing options.© 2024. The Author(s).