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Whole Exome Sequencing Identifying Causative Gene in a Intracranial Aneurysm Pedigree

Author: YuJun
Tutor: ZhangJianMin
School: Zhejiang University
Keywords: intracranial aneurysm pedigree whole exome sequencingcausative gene
CLC: R3411
Type: PhD thesis
Year: 2013
Downloads: 34
Quote: 0
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BackgroundCerebrovascular disease is one of the three most common diseases in mankind. The number of death caused by cerebrovascular disease accounts for the first place in China every year, a large portion of which are cerebral hemorrhage. Intracranial aneurysm (IA) rupture is the most common cause of cerebral hemorrhage. IA is the balloon or sac-like dilation of blood vessels inside the brain. These vascular anomalies pose potential risk of rupture leading to subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage has an annual incidence of10-15per100,000. Among those individuals who suffer a ruptured intracranial aneurysm,12%die befor treatment,40%die within one month,1/3patients have morbidity after survive. Intracranial aneurysm is a disease of high morbidity and mortality and still a major public health problem.IA is associated with many factors that can be classified into two major groups: first, a strong but complex genetic component, second, modifiable environment risk factors. Environmental factors include cigarette smoking, heavy alcohol consumption, drug abuse and hypertension. Although the genetic basis of IA is currently poorly understood, it has concluded that genetic factors play an important role in the pathogenesis of SAH and IAs. IA is a complicated disease with multiple genes and multi genetic models related, it can be influenced by environment factors.With the rapid advancement of the sequencing technique, the cost of sequencing is reducing correspongdingly, whole exome sequencing (WES) has been the most effective method to locate the genetic cause of diseases. WES is a high-performance method in detecting mutations in exome wide and according to the journal of "Science", WES was chosen as one of the top ten breakthroughs of science in2010. There have a lot of publications reporting using WES to find the genetics etiology of tumors, no research had published using WES to find the genetics etiology of IA. The appearance of WES brings evolution in methodology of genetic research of I A, and it is possible for us to find the pathogenic mutation in the level of exome wide.We collected an aneurysm pedigree in Caucasus population. There have5IA patients and3non-IA patients,4IA patients and3non-IA patients’genomic DNA was draw from the whole peripheral blood. We used whole exome sequencing and construct different models in statistical analysis to identify genetic mutations in this pedigree.Results:1、In complete penetrance model, we got two heterozygous mutation genes were shared by four patients. CMTM4、RXRA, but CMTM4are functionally inexplainable.2、In incomplete penetrance model, we got three heterozygous mutation genes were shared by four patients and some of other non-IA patients. SLC26A1、CCR2、 FAM129A.but FAM129A are functionally inexplainable.3、No homozygous of compound heterozygous mutation were shared by four patients in recessive model.4、Three mutation are novel in NHLBI database and nomoral population; Find a novel mutation on RARX in sporadic intracranial aneurysm.Conclusion:1、The strategy of "pedigree in identifying exome level mutations of IA in multiple models" is a feasible approach for genetic research of IA.2、The mutation of RXRA gene may be closely related to IA with the model of complete penetrance.3、The mutation of SLC26A1、CCR2gene may be the related to IA with the model of incomplete penetrance. Whole exome sequencing can be used to identify causative genes in aneurysm pedigree, using nomoral population and sporadic patients validat causative genes. There will be of great significance for early diagnosis, prevention and treatment of IA.

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