The Genetic Landscape of Diamond-Blackfan Anemia
The Genetic Landscape of Diamond-Blackfan Anemia
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DOI：
10.1016/j.ajhg.2018.10.027
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发表时间：
2018-12-06
影响因子：
9.8
通讯作者：
Gazda, Hanna T.
中科院分区：
文献类型：
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作者：
Ulirsch, Jacob C.;Verboon, Jeffrey M.;Gazda, Hanna T.
Diamond-Blackfan贫血（DBA）是一种罕见的骨髓衰竭性疾病，每1，000，000例活产中有7例受影响，并且与核糖体成分的突变有关。为了描述这种异质性疾病的遗传特征，我们招募了一组472名临床诊断为DBA的个体，并进行了全外显子组测序（WES）。我们为78%的个体确定了相关的罕见和预测的破坏性突变。大多数突变是单基因突变，在人群数据库中不存在，预测会导致功能丧失，并且位于先前报道的19个核糖体蛋白（RP）编码基因中的1个。使用外显子覆盖率估计，我们确定并验证了31个RP基因缺失。我们还观察到扩展剪接位点突变的富集，并使用从DBA个体获得的细胞系中的RNA测序验证了它们的不同作用。利用我们队列的规模，我们观察到基因型-表型与先天性异常和治疗结果之间存在强有力的相关性。我们进一步确定了7个以前未报道的可能导致DBA的RP基因中的罕见突变，以及几种出现表型DBA的不同疾病，包括9个具有导致ADA 2缺乏的双等位基因CECR 1突变的个体。然而，在全外显子组显著性上没有鉴定出新的基因，这表明不存在含有容易通过WES鉴定的突变的未鉴定的基因，其解释>5%的DBA受影响的病例受试者。总体而言，本报告不仅应告知DBA受影响个体的临床实践，还应告知异质性孟德尔疾病罕见变异研究的设计和分析。
Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.