本文選題：肥厚型心肌病 + 家族性��； 參考：《北京協(xié)和醫(yī)學院》2014年博士論文

【摘要】：研究背景 肥厚型心肌病(hypertrophic cardiomyopathy, HCM)是由于單基因突變而導致的常染色體顯性遺傳性疾病,主要表現(xiàn)為左心室和(或)右心室及室間隔不對稱肥厚、心室腔變小、心室順應性降低。是青少年和運動員心源性猝死(Sudden cardiac death,SCD)最常見原因,可在任何年齡段發(fā)病,有顯著的家族聚集性,家族性發(fā)病者占全部病例的50%,年死亡率約為1%-2%,具有發(fā)病年齡、發(fā)病程度和猝死風險等臨床表型多樣性的特點。研究發(fā)現(xiàn)：相關突變基因主要定位在β肌球蛋白重鏈基因、肌球蛋白結合蛋白C基因、心臟肌鈣蛋白T基因等肌小節(jié)蛋白基因以及相關的線粒體基因與修飾基因上,超過900種不同的基因突變類型與HCM發(fā)生發(fā)展以及臨床表型有關。目前在已經明確導致HCM的基因中發(fā)現(xiàn)至少1400個突變位點。指南中8個明確導致HCM的基因為p肌球蛋白重鏈(MYH7)、肌球蛋白結合蛋白c(MYBPC3)、肌鈣蛋白T(TNNT2)、肌鈣蛋白I(TNNI3)、a肌球蛋白(TPM1)、肌動蛋白(ACTC)、調節(jié)輕鏈(MYL2)和基本輕鏈基因(MYL3)。其中p肌球蛋白重鏈基因(MYH7)、肌球蛋白結合蛋白C基因(MYBPC3)及心臟肌鈣蛋白T基因(TNT)是最常見的3個HCM致病基因,由這些基因突變引起的HCM約占75%。 傳統(tǒng)的Sanger法測序是遺傳病分子診斷的金標準,但是將已知候選基因進行逐一排查耗時、費力及價格昂貴,特別是HCM基因比較多而且復雜。第二代高通量基因測序(Next generation squencing, NGS)以高通量、速度快、低成本為主要特征,可直接通過聚合酶或連接酶進行體外測序合成。運用NGS方法,不僅能檢測到遺傳性疾病的致病基因突變,而且能夠發(fā)現(xiàn)新的基因或突變,全面地勾勒出基因組上的變異圖譜。 研究目的 對家族性肥厚型心肌病患者進行第二代測序和家系驗證,來分析家族性肥厚型心肌病患者的的致病基因及突變位點,分析基因型與臨床表型及預后的關系。 研究方法 應用二代測序方法對家族性肥厚型心肌病家系的先證者進行基因檢測,根據(jù)測序結果設計目標基因片段的引物,對患者及其家系成員進行第一代Sanger測序,即聚合酶鏈式反應擴增其功能區(qū)外顯子片斷,雙脫氧末端終止法測序。分析該家系中所有患者的臨床表型特點,并對其進行臨床隨訪。 研究結果 1個肥厚型心肌病家系的先證者經第二代測序檢測發(fā)現(xiàn)MYH7基因的18號外顯子上c.1987GA突變,導致精氨酸變?yōu)榘腚装彼?即Arg663Cys (R663C)。對其家系中其他成員進行基因篩查,全部進行p肌球蛋白重鏈(MYH7)18號外顯子的目的基因片段的篩查,其中有4個家系成員同時有Arg663Cys突變,而正常對照組在同一位置未見異常。該家系患者臨床表現(xiàn)為活動后胸悶伴暈厥或猝死,呈惡性表現(xiàn),先證者進行了改良的Morrow外科手術,術后癥狀消失,臨床隨訪2年,患者恢復良好,無活動后胸悶胸痛不適,超聲心動圖未發(fā)現(xiàn)進展性改變。 另外1個肥厚型心肌病家系的先證者經第二代測序檢測發(fā)現(xiàn)MYBPC3基因的14號外顯子上新的移碼突變c.1374delC,移碼在465號氨基酸終止,終止密碼(TGA),即p.Arg458ArgfsX8(p.R458Rfs),該突變?yōu)槭澜缟鲜状螆蟮�。對其家系中其他成員進行Sanger測序,其中有3個家系成員同時有p.R458Rfs突變,而正常對照組在同一位置未見異常。該家系患者臨床表現(xiàn)和預后有異質性,先證者及其弟弟表現(xiàn)為活動后胸悶,先證者的母親和小姨已猝死,而其妹妹和女兒僅為突變攜帶者,無臨床表現(xiàn)。 結論 p肌球蛋白重鏈基因的18號外顯子突變Arg663Cys是家系1的致病突變。Arg663Cys所致肥厚型心肌病的臨床癥狀出現(xiàn)早,多合并左室流出道的梗阻,容易出現(xiàn)暈厥、猝死等不良事件,預后較差,但是積極地進行手術治療可緩解癥狀并能改善預后。 家系2的致病突變是MYBPC3基因的14號外顯子上新的移碼突變c.1374delC突變,p.R458Rfs,該突變?yōu)槭澜缟鲜状螆蟮?該突變的表型有異質性,預后不同。 研究背景 肥厚型心肌病是一種以左室非對稱性肥厚為特征的原發(fā)性心肌病,其主要并發(fā)癥有心房血栓、心律失常、心衰和猝死,但合并左室血栓的肥厚型心肌病臨床報道較少,本研究分析阜外心血管病醫(yī)院10年間有左室血栓的肥厚型心肌病患者的臨床資料,并探討其臨床特征、治療及預后情況,為臨床工作提供參考。 研究目的 探討經心臟核磁證實合并有左心室血栓的肥厚型心肌病(Hypertrophic cardiomyopathy, HCM)患者的臨床特征和預后情況。 研究方法 回顧性分析阜外心血管病醫(yī)院2002年1月～2012年12月住院病人中經心臟核磁共振(cardiac magnetic resonance, CMR)證實有左室血栓的HCM患者的臨床資料,并進行臨床隨訪。 研究結果 經心臟核磁證實有左室血栓的HCM患者共6例(血栓組),無左室血栓的HCM患者共284例(無血栓組),血栓組的家族史比例、室性心律失常、左房內徑、左室內徑和室壁瘤明顯高于無血栓組(p0.05),而左室射血分數(shù)和流出道梗阻比例明顯低于無血栓組(p0.05)。有左室血栓的患者接受華法令抗凝治療,隨訪17～59月,未發(fā)現(xiàn)血栓栓塞,2例復查血栓消失,3例死亡,1例進行了全心臟移植。 結論 肥厚型心肌病合并左室血栓見于有室壁瘤或左室射血分數(shù)低下的患者,多合并室性心律失常,預后差；可發(fā)生栓塞事件,華法令可有效治療左室血栓。 背景： 假肥大型肌營養(yǎng)不良癥是由抗肌萎縮蛋白基因突變所致的一種X連鎖隱性遺傳神經肌肉疾病,又稱為杜氏或貝克肌營養(yǎng)不良(Duchenne's or Becker's muscular dystrophy, DMD or BMD),是以緩慢進行性加重的對稱性肌無力和肌萎縮為特點的遺傳性肌肉病變,其中DMD病情嚴重,預后差；BMD病情進展相對緩慢,可累及心臟。 目的： 總結假肥大型肌營養(yǎng)不良癥伴心臟擴大患者家系的臨床特征并進行基因診斷、分析和治療及預后,為臨床診治提供借鑒。 方法： 對假肥大型肌營養(yǎng)不良癥伴心臟擴大的先證者和家系成員進行血清肌酶、肌電圖、心電圖、心臟彩色超聲檢查及心臟核磁等臨床檢查,并采用Sanger直接測序的方法進行抗肌萎縮蛋白基因突變的檢測,同時對100例無血緣關系的健康人群進行該位點的基因擴增測序,以排除所發(fā)現(xiàn)的突變?yōu)槲粗巳憾鄳B(tài)位點的可能。對確診患者根據(jù)病情進行對癥治療并對其進行隨訪。 結果： 先證者符合BMD診斷,基因檢測結果提示先證者攜帶dystrophin基因突變(c.4998_5000Del GCA,p.1667delAla,為首次報道)。家系成員中檢測出3例患者攜帶以上突變,攜帶者均表現(xiàn)為四肢近端肌肉萎縮、無力,雙側腓腸肌假性肥大,血清肌酶的水平顯著增高,心臟均受累,先證者表現(xiàn)為晚期心衰,并進行心臟移植手術,后恢復良好。 結論： 基因檢測可為假肥大型肌營養(yǎng)不良癥先證者及其家系成員進行明確診斷；對于假肥大型肌營養(yǎng)不良癥伴心臟擴大引起心力衰竭的患者進行心臟移植術是治療晚期患者可行有效的方法。
[Abstract]:Background of the study

The most common causes of cardiac death ( MYH7 ) , myosin binding protein C ( MYBPC3 ) , troponin T ( TNNT2 ) , troponin I ( TNNI3 ) , myosin binding protein C ( MYBPC3 ) and cardiac troponin T gene ( TNT ) are the most common causes of these mutations .

The traditional Sanger method sequencing is a gold standard for molecular diagnosis of genetic diseases , but the known candidate genes are sequenced one by one , time consuming , labor - consuming and expensive , in particular with more and more complex gene products . The second generation of high - throughput gene sequencing ( NGS ) is mainly characterized by high flux , high speed and low cost , and can be directly synthesized by using polymerase or ligase in vitro .

Purpose of study

Second - generation sequencing and pedigree verification of familial hypertrophic cardiomyopathy were performed to analyze the pathogenic gene and mutation sites of familial hypertrophic cardiomyopathy , and analyze the relationship between genotype and clinical phenotype and prognosis .

Research Methods

First - generation Sanger sequencing was performed on the first - generation Sanger sequencing of patients and their family members according to the sequencing results . The clinical phenotype characteristics of all patients in the family were analyzed and their clinical follow - up was performed .

Results of the study

The mutation of c . 1987GA was found on the exon 18 of MYH7 gene by second - generation sequencing , leading to the mutation of Arg663Cys ( R663C ) .

One of the other members of the family of hypertrophic cardiomyopathy were identified by the second - generation sequencing . The new transcoders were found on the exon 14 of the MYBPC3 gene . The mutation was the first report in the world . The mutation was the first report in the world . The mutation was the first report in the world . The other members of the family were sequenced . The clinical manifestations and prognosis of the family were heterogeneous . The first proband and his younger brother were sudden death , while their sister and daughter were only the mutation carriers , and no clinical manifestation .

Conclusion

Arg663Cys , the exon 18 of the heavy chain gene of p - myosin heavy chain , is the pathogenic mutation of family 1 . The clinical symptoms of hypertrophic cardiomyopathy caused by Arg663Cys occur early , complicated with obstruction of left ventricular outflow tract , syncope , sudden death and other adverse events , and poor prognosis .

The pathogenic mutation of family 2 is a new mutation in the exon 14 of MYBPC3 gene , c . 1374delC mutation , p . R458Rfs , which is the first report in the world . The mutation has heterogeneity and different prognosis .

Background of the study

Hypertrophic cardiomyopathy is a primary cardiomyopathy characterized by left ventricular asymmetric hypertrophy . The main complications are atrial thrombosis , arrhythmia , heart failure and sudden death , but the clinical data of hypertrophic cardiomyopathy combined with left ventricular thrombus is less , and the clinical features , treatment and prognosis of patients with left ventricular thrombus are analyzed in this study , and the clinical features , treatment and prognosis are discussed .

Purpose of study

To investigate the clinical characteristics and prognosis of patients with hypertrophic cardiomyopathy combined with left ventricular thrombus .

Research Methods

The clinical data of patients with left ventricular thrombus were confirmed by cardiac magnetic resonance ( CMR ) from January 2002 to December 2012 , and clinical follow - up was performed .

Results of the study

A total of 284 patients with left ventricular thrombus were confirmed by cardiac nuclear magnetic examination ( thrombus group ) , there were 284 patients without left ventricular thrombus ( no thrombus group ) , the proportion of family history of thrombus group , ventricular arrhythmia , left atrial diameter , left ventricular diameter and ventricular aneurysm were significantly lower than those without thrombus group ( p 0.05 ) .

Conclusion

Hypertrophic cardiomyopathy combined with left ventricular thrombus was seen in patients with ventricular aneurysm or left ventricular ejection fraction , with multiple ventricular arrhythmias and poor prognosis .
embolic events may occur , and warfarin is effective in the treatment of left ventricular thrombus .

Background :

Duchenne ' s or Becker ' s muscular dystrophy ( DMD or BMD ) is a hereditary muscular disease characterized by slow progressive weighted symmetry and muscular atrophy , in which DMD is serious and poor in prognosis .
The progression of BMD is relatively slow and can involve the heart .

Purpose :

To summarize the clinical characteristics of the patients with large muscular dystrophy accompanied by heart enlargement and to carry out gene diagnosis , analysis and treatment and prognosis to provide reference for clinical diagnosis and treatment .

Method :

In order to exclude the possibility of detecting the mutational site of the unknown population by using Sanger ' s direct sequencing method , the gene amplification and sequencing of 100 patients with unrelated healthy population were carried out to eliminate the possibility of the mutation being unknown .

Results :

The probands were diagnosed with BMD , and the results of gene detection suggested that the probands carry the gene mutation ( c . 4998 _ 5000Del , p . 1667delAla , for the first time ) . In the family members , 3 patients were detected to carry the above mutation , and the carriers were characterized by atrophy of the proximal muscle of the limbs , weakness of weakness , pseudohypertrophy of the bilateral calf muscle , a significant increase in the level of serum muscle enzyme , and the heart all affected . The former showed advanced heart failure and underwent heart transplantation and recovered well after heart transplantation .

Conclusion :

Gene detection can be used to make clear diagnosis for the proband and family members of the large muscular dystrophy of pseudo - fertilizer .
Heart transplantation is a feasible and effective method for patients with advanced heart failure due to large muscular dystrophy accompanied by heart enlargement .
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R542.2;R746.2

【參考文獻】

相關期刊論文 前1條

1 葛均波;崔潔;;無創(chuàng)檢查在肥厚型心肌病診斷中的應用[J];國際心血管病雜志;2011年01期

，

本文編號：2036806