Genetic diagnostic tools including whole-exome sequencing (WES) have advanced our understanding in human diseases and become common practice in diagnosing patients with suspected primary immune deficiencies. Establishing a genetic diagnosis is of paramount importance for tailoring adequate therapeutic regimens, including identifying the need for hematopoietic stem cell transplantation (HSCT) and genetic-based therapies. Here, we genetically studied two adult patients who were clinically diagnosed during infancy with severe combined immune deficiency (SCID). Two unrelated patients, both of consanguineous kindred, underwent WES in adulthood, 2 decades after their initial clinical manifestations. Upon clinical presentation, immunological workup was performed, which led to a diagnosis of SCID. The patients presented during infancy with failure to thrive, generalized erythematous rash, and recurrent gastrointestinal and respiratory tract infections, including episodes of Pneumocystis pneumonia infection and Candida albicans fungemia. Hypogammaglobulinemia and T-cell lymphopenia were detected. Both patients were treated with a 10/10 HLA matched sibling donor unconditioned HSCT. Retrospective genetic workup revealed homozygous bi-allelic mutations in IL7RA in one patient and in RAG2 in the other. Our study exemplifies the impact of retrospectively establishing a genetic diagnosis. Pinpointing the genetic cause raises several issues including optimized surveillance and treatment, understanding disease mechanisms and outcomes, future family planning, and social and psychological considerations.

包括全外显子组测序 (WES) 在内的基因诊断工具加深了我们对人类疾病的理解，并成为诊断疑似原发性免疫缺陷患者的常见做法。建立基因诊断对于定制适当的治疗方案至关重要，包括确定造血干细胞移植 (HSCT) 和基于基因的治疗的需求。在这里，我们对两名在婴儿期临床诊断为严重联合免疫缺陷 (SCID) 的成年患者进行了基因研究。两名不相关的患者，都是近亲，在成年后接受了 WES，在他们最初的临床表现后 20 年。临床表现后，进行免疫检查，诊断为SCID。肺孢子菌肺炎感染和白色念珠菌真菌血症。检测到低丙种球蛋白血症和 T 细胞淋巴细胞减少。两名患者均接受了 10/10 HLA 匹配的同胞供体无条件 HSCT 治疗。回顾性基因检查显示，一名患者的IL7RA和另一名患者的RAG2中存在纯合双等位基因突变。我们的研究举例说明了回顾性建立基因诊断的影响。查明遗传原因引发了几个问题，包括优化监测和治疗、了解疾病机制和结果、未来的计划生育以及社会和心理考虑。