Rozevska Marija, Daila Neiburga-Vigante Katrina, Nartisa Inga, Lucane Zane, Ozola Lota, Bardina Livija, Jaunalksne Inta, Gerula Natalija, Krike Petra, Taurina Gita, Nokalna-Spale Ieva, Micule Ieva, Vilne Baiba, Kisand Kai, Pajusalu Sander, Gailite Linda, Rots Dmitrijs, Kurjane Natalja
Institute of Oncology and Molecular Genetics, Riga Stradiņš University, Riga, Latvia.
Children's Clinical University Hospital, Riga, Latvia.
Front Immunol. 2025 Mar 28;16:1510365. doi: 10.3389/fimmu.2025.1510365. eCollection 2025.
Inborn errors of immunity (IEI), a diverse group of rare inborn disorders involving over 500 genes, pose diagnostic challenges despite next-generation sequencing advancements. Accurate molecular diagnosis is crucial for personalized treatment. This study aimed to assess the complementary role of genome and transcriptome sequencing in improving diagnostic yield for inborn errors of immunity. A cohort of 37 suspected IEI cases mainly consisting of predominantly primarily antibody deficiency (PAD) (27/37) underwent genome and transcriptome sequencing. We validated transcriptome sequencing analysis using positive controls and showed limitations of current methods. Among the 37 IEI cases, genetic etiology was identified in 14% (5/37). Genome and transcriptome sequencing prompted diagnostic changes in three initially diagnosed common variable immunodeficiency (CVID)/PAD cases, including showing RAS-associated autoimmune leukoproliferative disorder presenting as a novel CVID mimic disorder. The spectrum of identified pathogenic variants included , , , , and . A complex structural variant in was characterized, demonstrating the significance of transcriptome sequencing in clarifying the genomic findings. While genome and transcriptome sequencing provided critical insights and allowed to provide correct diagnosis for at least 14% of the patients, the overall improvement in diagnostic yield over exome sequencing is limited. Transcriptome sequencing proved efficient in variant effect interpretation. Our findings underscore the evolving landscape of primary immunodeficiency genetics, necessitating ongoing exploration for novel genes and atypical phenotypes. The integration of genome and transcriptome sequencing holds promise but requires further refinement to enhance the diagnostic yield.
遗传性免疫缺陷病（IEI）是一组涉及500多个基因的罕见遗传性疾病，尽管有新一代测序技术的进步，但仍面临诊断挑战。准确的分子诊断对于个性化治疗至关重要。本研究旨在评估基因组和转录组测序在提高遗传性免疫缺陷病诊断率方面的互补作用。一组37例疑似IEI病例主要由主要为原发性抗体缺陷（PAD）（27/37）组成，接受了基因组和转录组测序。我们使用阳性对照验证了转录组测序分析，并显示了当前方法的局限性。在37例IEI病例中，14%（5/37）确定了遗传病因。基因组和转录组测序促使3例最初诊断为常见变异型免疫缺陷（CVID）/PAD的病例发生诊断改变，包括显示RAS相关自身免疫性白细胞增殖性疾病表现为一种新的CVID模拟疾病。鉴定出的致病变异谱包括 、 、 、 、 和 。 中的一个复杂结构变异得到了表征，证明了转录组测序在阐明基因组发现方面的重要性。虽然基因组和转录组测序提供了关键见解，并能够为至少14%的患者提供正确诊断，但与外显子组测序相比，诊断率的总体提高有限。转录组测序在变异效应解释方面被证明是有效的。我们的发现强调了原发性免疫缺陷遗传学的不断发展，需要持续探索新基因和非典型表型。基因组和转录组测序的整合有前景，但需要进一步完善以提高诊断率。
