Riess Angelika, Roggia Cristiana, Selting Antje Schulze, Lysenkov Vladislav, Ossowski Stephan, Casadei Nicolas, Riess Olaf, Singh Yogesh
Institute of Medical Genetics & Applied Genomics, University Hospital Tübingen, Tübingen University, Tübingen, Germany.
NGS Competence Centre Tübingen, University Hospital Tübingen, Tübingen University, Tübingen, Germany.
Funct Integr Genomics. 2025 May 9;25(1):101. doi: 10.1007/s10142-025-01608-y.
Mulvihill-Smith Syndrome (MSS) is a clinically complex and genetically unsolved nano-rare disorder with only 12 patients reported in the literature. Most patients (91%) have immunological impairments, succumb to infection, and might develop cancer later in life. Its pathogenesis remains elusive and therapeutic options are limited. We used single-cell MULTI-omics (sc-MULTI-omics), combining transcriptomics (gene expression, TCR, and BCR repertoire) and proteogenomic (Cellular Indexing of Transcriptomes and Epitopes by Sequencing; CITE-seq), to decipher the pathophysiology of nano-rare disease patient. We report a new patient who is a 16-year-old girl. She had an increased leukocyte counts and typical manifestations of MSS such as short stature, older appearance, multiple pigmented nevi, microcephaly, monolateral keratoconus, Marcus-Gunn syndrome, hearing loss, vitamin D deficiency, mild hypercortisolism, and diabetes mellitus with very high insulin resistance (T3DM). sc-MULTI-omics CITE-seq showed that the MSS patient had increased central memory CD4 T cells as well as effector memory CD8 T cells, whilst reduced naïve T cells (both CD4 and CD8 T cells). Furthermore, we identified genes and pathways associated with the progeria-like phenotype, inflammation, and cancer progression, which may contribute to the clinical signs of MSS. sc-MUTLI-omics CITE-seq analyses improve our understanding of complex human disease pathophysiology and provides an alternative approach in personalized medicine in nano-rare disease.
马尔维希尔-史密斯综合征（MSS）是一种临床复杂且遗传机制未明的超罕见疾病，文献中仅报道了12例患者。大多数患者（91%）存在免疫功能障碍，易感染，且后期可能患癌症。其发病机制仍不清楚，治疗选择有限。我们使用单细胞多组学技术（sc-多组学），将转录组学（基因表达、TCR和BCR库）和蛋白质基因组学（通过测序进行转录组和表位的细胞索引；CITE-seq）相结合，来解读超罕见疾病患者的病理生理学。我们报告了一名16岁女孩的新病例。她白细胞计数升高，有MSS的典型表现，如身材矮小、面容苍老、多发色素痣、小头畸形、单侧圆锥角膜、马库斯-冈恩综合征、听力丧失、维生素D缺乏、轻度皮质醇增多症以及伴有极高胰岛素抵抗的糖尿病（T3DM）。sc-多组学CITE-seq显示，该MSS患者的中枢记忆CD4 T细胞以及效应记忆CD8 T细胞增多，而幼稚T细胞（CD4和CD8 T细胞均减少）。此外，我们确定了与早衰样表型、炎症和癌症进展相关的基因和通路，这可能导致了MSS的临床症状。sc-MUTLI-omics CITE-seq分析增进了我们对复杂人类疾病病理生理学的理解，并为超罕见疾病的个性化医疗提供了一种替代方法。
