本文關(guān)鍵詞： 小耳畸形 伴發(fā)畸形 遺傳特征 候選基因　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：目的先天性小耳畸形是體表重大畸形,嚴(yán)重影響患者的外貌和心理健康,進(jìn)行小耳畸形發(fā)病特征和相關(guān)遺傳學(xué)研究意義重大。本研究探討中國(guó)小耳畸形患者伴發(fā)畸形的發(fā)生情況和特點(diǎn),分析之間的關(guān)聯(lián);經(jīng)過(guò)對(duì)家族史的詳細(xì)調(diào)查,了解小耳畸形患者的遺傳特征;在小耳畸形患者中進(jìn)行候選基因序列變異和拷貝數(shù)變異檢測(cè),對(duì)變異進(jìn)行生物信息學(xué)分析。通過(guò)以上研究逐步深化對(duì)小耳畸形的認(rèn)知,可作為今后小耳畸形分子機(jī)制的研究和防治的基礎(chǔ)。方法1.在基于醫(yī)院的研究中選取2014年12月-2016年2月間小耳畸形患者,對(duì)所有非綜合征型小耳畸形患者672例進(jìn)行詳細(xì)地體格檢查,并記錄相關(guān)伴發(fā)畸形。將伴發(fā)畸形根據(jù)受影響的主要器官系統(tǒng)進(jìn)行分類(lèi),采用SPSS 19.0統(tǒng)計(jì)學(xué)軟件分析小耳畸形與伴發(fā)畸形間的關(guān)系。并與其他國(guó)家地區(qū)的小耳伴發(fā)畸形資料對(duì)比分析中國(guó)小耳群體患病特點(diǎn)。2.對(duì)上述672個(gè)患者通過(guò)查體、直接詢問(wèn)及電話隨訪的方法獲得患者的家系資料及耳部畸形發(fā)病情況并登記。主要調(diào)查對(duì)象為先證者、一級(jí)親屬、二級(jí)親屬、三級(jí)親屬、四級(jí)親屬,按照小耳畸形患者是否具有耳部畸形家族史背景分為家族史組和散發(fā)組,對(duì)數(shù)據(jù)進(jìn)行統(tǒng)計(jì)學(xué)分析,探尋有價(jià)值的規(guī)律。3.隨機(jī)選取200例散發(fā)小耳畸形患者對(duì)六個(gè)候選基因(HOXA1、HOXA2、EYA1、SIX1、SALL1、FGF3)進(jìn)行序列變異和拷貝數(shù)變異檢測(cè),并利用生物信息學(xué)分析變異的危害。結(jié)果1.本研究顯示了男性(72%)、單側(cè)(92.99%)和右側(cè)(63%)多發(fā),與文獻(xiàn)中的結(jié)果一致。我們?cè)?93(43.6%)位患者中發(fā)現(xiàn)了一項(xiàng)及以上的伴發(fā)畸形,尤其是耳面頸系統(tǒng)、肌肉骨骼系統(tǒng)、心血管系統(tǒng)伴發(fā)率最高。耳廓發(fā)育程度越差伴發(fā)畸形率越高。小耳不同伴發(fā)畸形比例有顯著異質(zhì)性,但大體在器官系統(tǒng)畸形方面的權(quán)重是相符的,即伴發(fā)畸形最常累及的是耳面頸系統(tǒng),接下來(lái)是肌肉骨骼系統(tǒng),然后是心血管系統(tǒng),后面是泌尿生殖系統(tǒng),呼吸系統(tǒng)、神經(jīng)系統(tǒng)、消化系統(tǒng)等較少累及。2.本研究中耳部畸形家族史陽(yáng)性率為34.1%,其中一級(jí)親屬所占比例最高,二、三、四級(jí)親屬比例依次減少,符合遺傳學(xué)規(guī)律,且父母兩系背景在各級(jí)小耳畸形患者人數(shù)構(gòu)成比無(wú)統(tǒng)計(jì)學(xué)差異。有33.8%小耳畸形患者伴發(fā)附耳/瘺管,且這部分患者比單純小耳患者有更高的家族耳部畸形發(fā)生率。3.在200例患者中,鑒定出1例患者HOXA2基因的錯(cuò)義突變(c.260CT,p.A87V),此突變不存在于患者父母,為新發(fā)突變,在1000 human genome、HGMD、ESP6500、dbSNP和ExAC等數(shù)據(jù)庫(kù)中未查到相關(guān)記錄,經(jīng)生物信息學(xué)分析該突變高度保守,推測(cè)其具有致病性。檢測(cè)到兩例患者存在EYA1基因的拷貝數(shù)缺失,推測(cè)為小耳畸形的致病原因。結(jié)論1.本研究是中國(guó)小耳患者中第一份有關(guān)伴發(fā)畸形的詳細(xì)專(zhuān)題性研究,小耳患者的伴發(fā)畸形率較高,且臨床異質(zhì)性較大,為了探索小耳畸形病因及為患者提供更好的治療,應(yīng)加大未來(lái)對(duì)相關(guān)伴發(fā)畸形的研究力度。2.本研究結(jié)合其他耳部畸形多發(fā)性,將家屬耳部畸形納入研究并證實(shí)耳部畸形家族史發(fā)生率為34.1%,且存在垂直傳遞、隔代遺傳和家族聚集的遺傳特征。在研究小耳畸形遺傳特征時(shí)不應(yīng)忽略親屬中的其他耳畸形。雖然小耳畸形目前發(fā)病機(jī)制不明,但遺傳因素不容忽視。3.本研究分別對(duì)200例散發(fā)小耳患者六個(gè)候選基因進(jìn)行了序列變異和拷貝數(shù)變異檢測(cè),成功地鑒定了一例患者存在HOXA2基因編碼區(qū)的c.260CT(p.A87V)突變,此突變位于exon1,為國(guó)際首次報(bào)道,擴(kuò)增了小耳畸形HOXA2基因突變譜;并且在兩例患者中檢測(cè)到EYA1基因拷貝數(shù)缺失。這些發(fā)現(xiàn)可能是小耳畸形的致病因素,其發(fā)病機(jī)制,有待下一步研究驗(yàn)證。
[Abstract]:The purpose of congenital microtia is a major body deformity, seriously affect the patient's appearance and mental health, study significance of microtia disease characteristics and related genetics. Major of this study was to investigate the occurrence and characteristics of deformity with Chinese microtia patients, correlation analysis between; after a detailed investigation of family history, understand the genetic characteristics of patients with microtia; and the copy number variation of candidate gene sequence variation detection in patients with microtia, bioinformatics analysis of variation. Through the above study, the gradual deepening of the microtia cognition, can be used as a basis for future research and the prevention of microtia molecular mechanism. Methods 1. in December 2014 select the -2016 in February of microtia patients in hospital in the study based on the physical examination of 672 cases with all non syndromic patients with microtia, and record The associated malformation accompanied malformations. According to the main organ system affected the classification, using SPSS 19 statistical software to analyze the relationship between microtia and associated malformations. With comparative analysis of the data Chinese small ear malformation group prevalence characteristics of.2. of the 672 patients through the examination with other countries and regions of the small ear method, direct examination and telephone follow-up for patients with family data and ear deformity incidence and registration. The main research object for the proband, first-degree relatives, two relatives, three relatives, four relatives, according to the patients with microtia is not with ear deformity family history background into family history group and the sporadic group, the statistical analysis of the data, to explore the value of.3. in 200 randomly selected patients with sporadic microtia in six candidate genes (HOXA1, HOXA2, EYA1, SIX1, SALL1, FGF3) sequence variation and copy number variation Abnormal detection, and the use of bioinformatics analysis of variation of harm. 1. results of this study shows that male (72%), unilateral (92.99%) and right (63%) multiple, consistent with the results in the literature. We in 293 (43.6%) patients were found in one or more of the associated anomalies, especially the ear is the face and neck system, musculoskeletal system, cardiovascular system and the incidence rate of the highest degree of development. The worse ear malformations was higher. Small ear malformations have significantly different proportion of heterogeneity, but generally in the organ system abnormalities weight is consistent, which is associated with the most frequently involved is deformity next is the ear of face and neck system, musculoskeletal system, and then is behind the cardiovascular system, genitourinary system, respiratory system, nervous system, digestive system and the positive rate of less involved.2. this study of middle ear malformation family history was 34.1%, of which the first-degree relatives of the highest proportion, two, three, four In order to reduce the proportion of relatives, comply with the laws of genetics, and the parental background at all levels of two-line microtia patients who showed no significant difference. There are 33.8% patients with fistula / ear hair with microtia, and these patients than microtia patients had a higher incidence of.3. family ear deformity in 200 patients, 1 patients identified missense mutations in the HOXA2 gene (c.260CT, p.A87V), this mutation does not exist in patients with parents, is a new mutation in 1000 human, genome, HGMD, ESP6500, dbSNP and ExAC in the database did not find relevant records, by bioinformatics analysis of the mutations are highly conserved, presumably with pathogenicity. Two patients have detected EYA1 gene copy number is missing, presumed cause of microtia. Conclusion: 1. this study is Chinese with the first small ear malformations with the special study, patients with small ears The malformation rate is higher, and the heterogeneity is larger, in order to explore the microtia etiology and provide better treatment for patients, should increase the future of related research efforts with.2. deformity combined with the other ear deformity of multiple family members, will be included in the study and confirmed that the ear ear deformity deformity of the family history of incidence was 34.1%. And there are vertical transmission, genetic characteristics of atavism and family aggregation. In the study of genetic characteristics of microtia should not ignore other relatives in ear microtia malformation. Although the pathogenesis is unknown, but genetic factors can not be ignored in this study were.3. in 200 cases of sporadic microtia and six candidate genes were and copy number variation detection of sequence variation, successfully identified HOXA2 gene encoding region in a patient with c.260CT (p.A87V) mutation, the mutation in exon1, reported for the first time international, the amplification of microtia H OXA2 gene mutation spectrum and EYA1 gene copy number deletion were detected in two patients. These findings may be the pathogenic factors of microtia, and its pathogenesis needs further research and verification.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R764.7

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本文編號(hào)：1554787