家族性MDS/AML易患综合征家系的高效筛查与易患基因的鉴定

Genetic resources from families with familial MDS/AML predisposition syndromes are unique and highly appreciated. Researches on these inherited diseases would aid in the delineation of the underlying mechanisms of the sporadic cases of leukemia. But few pedigrees have been reported due to inadequate attention and non-effective screening strategies. Only five genes have been associated with susceptibility to MDS/AML thus far. However, the culprit genes in the majority of MDS/AML pedigrees remain obscure. Thus, additional pedigrees are required to fully delineate the mutation landscape of MDS/AML predisposition syndromes. We previously identified up to 23 MDS/AML pedigrees. Among them, two were highly penetrant AML families, which would provide sufficient samples for us to identify novel MDS/AML-predisposing genes. Based on these experience, we will exhausted our effort to establish an efficient strategy to find new pedigrees with MDS/AML susceptibility through mutation screening of known MDS/AML-predisposing genes, family history collecting with a simple questionnaire, and retrospectively medical record retrieval. Moreover, we will perform a whole exome sequencing on a multi-case AML family to identify novel MDS/AML-predisposing genes and enrich the mutation landscape of MDS/AML-predisposing syndromes. This study would promote our understanding and researches in MDS/AML predisposing families, and meanwhile provide considerable genetic resources for the researches of leukemogenesis.

家族性MDS/AML易患综合征具有独特的基因资源，对其深入研究有助于揭示散发白血病的发病机制。既往对这类疾病重视不够，筛查策略不完善，此类家系很少被发现，至今仅五个MDS/AML易患基因被鉴定出来。但多数家系无这些基因突变，因此有待更多家系的研究以描绘更详尽的白血病易患基因突变图谱。课题组前期在国内首次发现多达23个MDS/AML家系，其中2个为高发家系，为我们筛查和鉴定新的MDS/AML易患基因提供了充足的样本资源。在此基础上，本研究拟综合MDS/AML易患基因突变初筛、家族史简易调查表筛查、回顾性病案检索三方法，最大限度挖掘白血病家系，建立一套临床行之有效的家族性MDS/AML易患家系初筛策略。此外，通过外显子组测序1个AML高发家系，鉴定新的AML易患基因，丰富白血病易患基因突变图谱。该课题研究将促进人们对MDS/AML易患家系的认识与研究，并为白血病发病机制的研究提供大量基因资源。

家族性MDS/AML易患综合征具有独特的基因资源，对其深入研究有助于揭示散发白血病的发病机制。既往对这类疾病重视不够，筛查策略不完善，此类家系很少被发现，至今仅五个MDS/AML易患基因被鉴定出来。但多数家系无这些基因突变，因此有待更多家系的研究以描绘更详尽的白血病易患基因突变图谱。课题组前期发现一个白血病相关的肿瘤高发家系（3代4例白血病4例实体瘤），本项目通过对该家系的实地调查及随访，明确遗传因素为该家系的主要致病因素。在此基础上，对家系中4例患者（2例AML和2例实体瘤）、2个健康成员和2个婚入成员共8个人，进行了全基因组测序。利用生物信息学技术，采用不同策略，包括按不同遗传模式分析，按不同功能模式分析，遗传性拷贝数变异分析等，最终筛选出4候选基因变异，并进行了sanger测序验证，明确WT1基因变异与疾病表型共分离，为该家系可能的遗传致病变异。另外，本项目通过结合回顾性病案检索、家族史简易调查表筛查、MDS/AML易患基因突变初筛三方法，建立了一套家族性MDS/AML易患家系初筛策略，并发现29个白血病相关的肿瘤易患家系，采集到其中8个家系的先证者血样，为后期验证新发现的白血病易患基因提供了珍贵的样本资源。本项目通过建立有效的家族性MDS/AML易患家系初筛体系，收集到了稀缺的遗传性白血病易患家系资源，从一个高发家系的深入研究中发现了候选遗传致病基因，对该项目的继续推进，将有助于MDS/AML 发生的早期事件、“二次事件”的发现及MDS/AML 发病机制的揭示。

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