Mirabello Lisa, Khincha Payal P, Ellis Steven R, Giri Neelam, Brodie Seth, Chandrasekharappa Settara C, Donovan Frank X, Zhou Weiyin, Hicks Belynda D, Boland Joseph F, Yeager Meredith, Jones Kristine, Zhu Bin, Wang Mingyi, Alter Blanche P, Savage Sharon A
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA.
J Med Genet. 2017 Jun;54(6):417-425. doi: 10.1136/jmedgenet-2016-104346. Epub 2017 Mar 9.
Diamond-Blackfan anaemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterised by erythroid hypoplasia. It is associated with congenital anomalies and a high risk of developing specific cancers. DBA is caused predominantly by autosomal dominant pathogenic variants in at least 15 genes affecting ribosomal biogenesis and function. Two X-linked recessive genes have been identified.
We aim to identify the genetic aetiology of DBA.
Of 87 families with DBA enrolled in an institutional review board-approved cohort study (ClinicalTrials.gov Identifier:NCT00027274), 61 had genetic testing information available. Thirty-five families did not have a known genetic cause and thus underwent comprehensive genomic evaluation with whole exome sequencing, deletion and CNV analyses to identify their disease-associated pathogenic variant. Controls for functional studies were healthy mutation-negative individuals enrolled in the same study.
Our analyses uncovered heterozygous pathogenic variants in two previously undescribed genes in two families. One family had a non-synonymous variant (p.K77N) in ; the second family had a non-synonymous variant (p. L51S) in . Both of these variants result in pre-rRNA processing defects. We identified heterozygous pathogenic variants in previously known DBA genes in 16 of 35 families. Seventeen families who underwent genetic analyses are yet to have a genetic cause of disease identified.
Overall, heterozygous pathogenic variants in ribosomal genes were identified in 44 of the 61 families (72%). De novo pathogenic variants were observed in 57% of patients with DBA. Ongoing studies of DBA genomics will be important to understand this complex disorder.
钻石黑范贫血（DBA）是一种遗传性骨髓衰竭综合征（IBMFS），其特征为红系造血发育不全。它与先天性异常以及发生特定癌症的高风险相关。DBA主要由至少15个影响核糖体生物合成和功能的基因中的常染色体显性致病变异引起。已鉴定出两个X连锁隐性基因。
我们旨在确定DBA的遗传病因。
在一项经机构审查委员会批准的队列研究（ClinicalTrials.gov标识符：NCT00027274）中登记的87个患有DBA的家庭中，61个有可用的基因检测信息。35个家庭没有已知的遗传病因，因此接受了全外显子组测序、缺失和拷贝数变异分析的全面基因组评估，以确定其疾病相关的致病变异。功能研究的对照是参与同一研究的健康的无突变个体。
我们的分析在两个家庭中发现了两个先前未描述基因中的杂合致病变异。一个家庭在 中有一个非同义变异（p.K77N）；第二个家庭在 中有一个非同义变异（p.L51S）。这两个变异均导致前体核糖体RNA加工缺陷。我们在35个家庭中的16个家庭的先前已知的DBA基因中发现了杂合致病变异。接受基因分析的17个家庭尚未确定疾病的遗传病因。
总体而言，61个家庭中的44个（72%）鉴定出核糖体基因中的杂合致病变异。57%的DBA患者中观察到新生致病变异。对DBA基因组学的持续研究对于理解这种复杂疾病很重要。
