Gianferante D Matthew, Mendez Kyra J W, Cole Sarah, Gadalla Shahinaz M, Alter Blanche P, Savage Sharon A, Giri Neelam
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH, Rockville Bethesda Maryland USA.
Department of Pediatrics Uniformed Services University of the Health Sciences Bethesda Maryland USA.
EJHaem. 2024 Oct 16;5(6):1117-1124. doi: 10.1002/jha2.1031. eCollection 2024 Dec.
Diamond Blackfan anaemia (DBA) is a rare disorder characterized by failure of red blood cell production, congenital abnormalities and cancer predisposition, primarily caused by pathogenic germline variants in genes encoding ribosomal proteins.
We conducted a genotype-phenotype and outcome study of 121 patients with DBA spanning the 20-year history of the National Cancer Institute's Inherited Bone Marrow Failure Syndromes study. Patient phenotypes were compared by large versus small ribosomal protein genes, across genes with >5 cases (, , and ) and by type of pathogenic variants (hypomorphic versus null, large deletions versus others).
A pathogenic germline variant was identified in 71% of patients ( = 86/121) from 54 families. After adjusting for multiple testing, we found that patients with variants were least likely to need treatment for anaemia while those with large ribosomal protein subunit variants had a higher proportion of intellectual disability and gastrointestinal abnormalities compared with small ribosomal protein subunit variants ( < 3.5 × 10). There were no statistically significant differences in overall survival or cancer incidence among patients with large or small ribosomal subunit genes.
This detailed genotype-phenotype study of DBA improves our understanding of the role of germline genetics in the clinical manifestations that may help guide the management of people with DBA.
钻石黑范贫血（DBA）是一种罕见疾病，其特征为红细胞生成障碍、先天性异常和癌症易感性，主要由编码核糖体蛋白的基因中的致病性种系变异引起。
我们对121例DBA患者进行了基因型-表型及转归研究，该研究涵盖了美国国立癌症研究所遗传性骨髓衰竭综合征研究的20年历史。通过大核糖体蛋白基因与小核糖体蛋白基因、病例数超过5例的基因（、、和）以及致病性变异类型（亚效等位基因与无效等位基因、大片段缺失与其他类型）对患者表型进行比较。
在来自54个家庭的71%（=86/121）的患者中鉴定出致病性种系变异。在进行多重检验校正后，我们发现携带变异的患者最不需要接受贫血治疗，而与小核糖体蛋白亚基变异相比，携带大核糖体蛋白亚基变异的患者智力残疾和胃肠道异常的比例更高（<3.5×10）。大核糖体亚基基因或小核糖体亚基基因的患者在总生存率或癌症发病率方面无统计学显著差异。
这项关于DBA的详细基因型-表型研究增进了我们对种系遗传学在临床表现中所起作用的理解，这可能有助于指导DBA患者的管理。
