MYH9相关综合征家系的临床表型和遗传学分析

目的 分析1组MYH9相关综合征家系的临床表现及遗传学特征.方法我们随访到1组4代51人的MYH9相关综合征家系,对目前存活的46人进行了临床表型和遗传学的初步分析.结果家系内有MYH9相关综合征患者17人,实验室检测都具有典型的"血小板减少、巨大血小板和粒细胞包涵体"三联症;临床表现具高度复杂性.并伴有严重的白血病、青光眼、转氨酶升高、血脂升高、哮喘、鼻炎及白内障等多种疾病,除此之外,本家系大部分感染者都有鼻炎和哮喘过敏史,而且当上述症状发作时,患者身上的出血点或紫癜会明显加重;在遗传方式上属于常染色体显性遗传.从细胞遗传学水平对家系中成员进行染色体检查,未发现核型异常.结论该MYH9相关综合征家系属常染色体显性遗传,染色体检查未发现核型异常;家系中的感染者不仅具有巨大血小板、血小板减少及中性粒细胞包涵体的特性,而且还具有严重的如:肝炎、白内障、白血痛、哮喘等临床表现.     

遗传性对称性色素异常症一家系ADAR基因突变研究

目的研究遗传性对称性色素异常症家系的RNA特异性的腺苷脱氨酶(RNA-specific adeno-sine deaminase,ADAR)基因的突变。方法收集一个遗传性对称性色素异常症家系的临床资料,采用聚合酶链反应及直接测序法对家系内成员进行ADAR基因突变位点检测,同时对50名无血缘关系健康对照者的该位点进行直接测序,并对国内外报道的ADAR基因突变进行总结。结果该家系中所有患者均存在ADAR基因c.2447G>A突变,导致p.R816K改变,而在家系内非患者及正常对照者中均未发现该突变。目前国内外已报道ADAR基因突变为64种。结论ADAR基因突变是中国人群中遗传性对称性色素异常的致病原因之一,ADAR基因各功能区域均可发生突变,但ADEAMc可能为其热点突变区域。     

遗传性牙釉质发育不全家系的调查与分析

采用家系调查方法对一牙釉质发育不全患者的家系情况进行了调查 ,并绘制成系谱图进行遗传学分析。结果发现该家系中连续 5代都出现该病患者 ,且患者子女中发病率近 1 /2 ,亦无性别差异 ,其传递方式符合常染色体显性遗传的特点 ;根据患者的临床表现 ,按照Witkop对该类口腔疾病的分类方法 ,该家系的疾病属于遗传性牙釉质发育不全中的第三种类型 ,即遗传性牙釉质矿化不全症     

1例遗传性抗凝血酶缺陷症导致复发性流产分析

目的 对1个新的SERPINC1基因杂合错义突变导致遗传性抗凝血酶缺陷症家系进行表型和基因突变分析,探讨此基因突变与复发性流产的关系.方法 收集先证者及其家系成员临床资料(共3代5人);检测先证者及家系成员的抗凝血酶活性(antithrombin activity,AT∶A)、抗凝血酶抗原(antithrombin a...     

儿童遗传性球形红细胞增多症19例临床分析——附一例家系调查

目的探讨儿童遗传性球形红细胞增多症临床特性、诊断要点;方法回顾性分析19例球形红细胞增多症患儿临床表现、实验室检查、治疗与转归,对其中1例患儿的基因突变类型与临床表型进行家系分离,分析该基因突变位点是否是该患儿致病基因;结果球形红细胞增多症典型病例根据血常规参数,溶血指标检查,多种生化实验检查,可诊断。实验室检查不能诊断的非典型疑难病例可行分子生物基因检测明确诊断;结论遗传性球形红细胞增多症遗传异质性明显,ANK1 c.399TG可能为其致病基因之一。     

遗传性非综合征型耳聋患者GJB2基因编码序列分析

目的 对6个遗传性非综合征型耳聋家系成员的GJB2基因编码序列进行分析,寻找耳聋患者的致病基因突变,探讨GJB2基因突变致病的遗传模式.方法 提取患者及家系成员的外周血基因组DNA,扩增GJB2基因的编码序列,然后对扩增产物进行DNA测序,对出现重叠峰形的扩增产物进行TA克隆后再测序,确定基因突变是否存在于同一拷贝.结果 6个遗传性非综合征型耳聋家系中,4个家系是GJB2基因突变所致.患者的GJB2基因突变包括235delC、299-300delAT、79G→A+341A→G和109G→A.非致聋突变79G→A与341A→G组合具有致聋效应,109G→A和235delC的杂合突变可能也有致聋效应.结论 GJB2基因突变致聋具有明显异质性,非致聋突变并非完全不致聋,环境因素或其它基因可能参与GJB2基因突变所致耳聋.     

COL4A5基因突变致X连锁Alport综合征的1例家系

Alport综合征是最常见的遗传性肾脏病之一。其临床表型除与该病相关的基因变异相关,还同其他基因状况、生活环境等因素密切相关,故即使同一家系中拥有相近基因型的个体也会出现不同的疾病表现。本研究对中国中医科学院广安门医院1例具有复杂家系的慢性肾脏病患者开展调查,收集患者及其家族成员临床资料,采用三代基因测序技术对患者及多位亲属的外周血DNA进行遗传学分析,结果显示家族中多人为COL4A5[c.152G>A(p.Gly51Glu)]基因突变导致的Alport综合征。文章就X连锁Alport综合征的临床特点及预后进行文献复习,结合对该家系多个受累成员发病情况分析,旨在提高临床医生对该病特点及遗传规律的认识。     

抗凝血酶基因10381T缺失导致的Ⅰ型抗凝血酶缺陷症

目的对1例遗传性抗凝血酶(AT)缺陷症先症者及其家系进行表型诊断和基因诊断,并探讨其家系成员发病机制。方法用发色底物法检测该家系9名成员的AT活性(AT∶A)、蛋白S活性(PS∶A)、蛋白C活性(PC∶A),用免疫比浊法检测AT抗原量(AT∶Ag),用Western blot检测血浆中的AT分子质量和含量,抽提外周血基因组DNA,用PCR对AT基因的7个外显子及其侧翼序列进行扩增,用直接测序法对该家系所有成员的扩增产物进行测序分析并进行基因突变检测,同时筛查100例正常人以排除基因突变的多态性。结果该家系先症者AT∶A和AT∶Ag分别为48%和121 mg/L,先症者AT基因的第6外显子发现10381T del。其家系的部分成员检测到相同的移码突变。结论该家系先症者及部分成员存在Ⅰ型遗传性抗凝血酶缺陷症,是由AT基因10381T del移码突变所致。     

一个遗传性对称性色素异常症家系ADAR1基因R1155W突变研究

目的 研究1个遗传性对称性色素异常症家系的ADAR1基因的突变.方法 收集1个遗传性对称性色素异常症家系的血样,采用聚合酶链反应结合DNA直接测序的方法,检测了该家系中2例患者及2名表型正常者和50名无亲缘关系健康个体的ADAR1基因突变情况.结果 该家系中2例患者均存在 ADAR1 基因c.3463C＞T突变,导致p.R1155W改变,而在家系内非患者及正常对照者中均未发现该突变.结论 本研究中遗传性对称性色素异常症家系中患者ADAR1基因存在错义突变,这可能是导致遗传性对称性色素异常症发病的分子机制之一.     

一个非综合征型唇腭裂家系的致病基因鉴定

目的对一个非综合征型唇腭裂家系进行分子遗传学研究,探寻其致病原因。方法对该家系成员进行详细的体格检查和既往史调查,排除综合征型唇腭裂。对该家系1例患儿的基因组DNA进行全外显子组测序及生物信息学分析。筛查到候选致病基因突变位点后,采用Sanger测序对该家系成员及100名健康对照个体进行共分离分析和人群验证分析。结果全外显子组测序及疾病共分离分析显示,该家系患者IRF6基因第4外显子存在c.253A>G(p.Cys85Arg)变异,且该突变未在健康对照个体中检出,文献尚未见报道。结论IRF6基因第4外显子c.253A>G错义变异是导致该家系发病的原因。     

46,XX男性综合征患者的细胞和分子遗传学研究

目的探讨SRY阳性的46,XX男性综合征患者的临床及细胞分子遗传学特征。方法对其外周血淋巴细胞进行染色体核型分析;同时提取外周血基因组DNA,进行SRY基因检测,并以正常男性及女性作对照。结果患者染色体核型为46,XX,SRY基因存在。结论基因组中存在SRY基因可能与该例46,XX男性综合征患者为男性表型密切相关,对其进行检测有利于明确性反转综合征的临床诊断,通过染色体核型分析和分子遗传学检测,可为性发育异常患者明确病因,并为其治疗提供依据。     

X-linked idiopathic thrombocytopenia

A family is described in which the incidence of thrombocytopenia suggested transmission by an X-linked gene. The condition carries a good prognosis. Comparison with previous similar reports suggests that the disorder is phenotypically distinct from the Wiskott-Aldrich syndrome.     

遗传性乳腺癌-卵巢癌临床分析

目的探讨遗传性乳腺癌-卵巢癌的遗传学、诊断及诊疗,为其早期诊断及正确治疗提供依据。方法总结遗传性乳腺癌-卵巢癌患者的临床资料,对其遗传学、早期诊断及治疗等方面进行探讨。结果遗传性乳腺癌-卵巢癌起源于甲状腺滤泡上皮细胞,它单独发生或作为家族性肿瘤综合征发生。多发性病灶和同时伴发腺瘤性甲状腺肿是其特征性临床表现,并且多发生在年轻人;合理的手术治疗可以取得满意的疗效。结论遗传性乳腺癌-卵巢癌是一种遗传性疾病,早期诊断、合理的手术治疗可以取得满意的疗效。患者家族成员应长期随访。     

The genotype of the original Wiskott phenotype

The Wiskott-Aldrich syndrome is an X-linked hereditary disorder associated with combined immunodeficiency, thrombocytopenia, small platelets, eczema, and increased susceptibility to autoimmune disorders and cancers. It is caused by mutations in the gene (WAS) for the Wiskott-Aldrich syndrome protein (WASP). We investigated family members of the patients originally described by Wiskott in 1937 and identified a new frame shift mutation in exon 1 of WAS. This mutation is likely to be the hypothesized genotype that caused the severe form of the Wiskott-Aldrich syndrome in the three brothers described by Wiskott.     

Deletion of the TWIST gene in a large five-generation family

In this article, we describe a large five-generation family with characteristics of the Saethre-Chotzen syndrome as well as of the blepharophimosis ptosis epicanthus inversus syndrome. Segregating with their phenotype is a deletion of the chromosome 7p21 TWIST gene locus. The TWIST gene indeed is involved in Saethre-Chotzen syndrome, a craniosynostosis syndrome further characterized by specific facial and limb abnormalities. However, only two members of our family exhibited craniosynostosis. This report demonstrates that the genetics of craniofacial anomalies are less straightforward than they sometimes appear to be. Not only craniosynostosis, but also subtle facial deformities could be indicative of an abnormality of the TWIST gene. In conclusion, the clinical spectrum of genetic abnormalities of the TWIST gene is highly variable. We therefore recommend that genetic analysis of the TWIST gene locus, including fluorescence in situ hybridization, should be considered in familial cases of facial and eyelid abnormalities without the presence of craniosynostosis.     

1.9 Mb microdeletion of 21q22.11 within Braddock-Carey contiguous gene deletion syndrome region: dissecting the phenotype

Braddock-Carey syndrome is characterized by Pierre Robin sequence, agenesis of the corpus callosum, facial dysmorphisms, developmental delay, and congenital thrombocytopenia. Recently, Braddock-Carey syndrome was demonstrated to be caused by chromosomal microdeletion in 21q22 including the RUNX1 gene, whose haploinsufficiency is responsible for thrombocytopenia phenotype. Therefore, the syndrome has emerged as a contiguous gene deletion syndrome. Here, we describe an infant with Pierre Robin sequence, facial anomalies, congenital heart defects, hypotonia, and the absence of thrombocytopenia, who was found to have a 1.9 Mb microdeletion within the Braddock-Carey contiguous deletion syndrome region. This deletion spares the RUNX1 gene, narrowing the genomic region responsible for a part of the Braddock-Carey syndrome phenotype. Further studies are awaited to understand the role of the genes located within 21q22 in the pathogenesis of Braddock-Carey syndrome.     

EYA1 nonsense mutation in a Japanese branchio-oto-renal syndrome family

Advances in molecular genetics have recently revealed that mutations in the EYA1 gene are responsible for branchio-oto-renal (BOR) syndrome in European and other populations. This is the first report confirming that an EYA1 gene mutation is also disease-causing in an Asian population. We have described one Japanese BOR syndrome family showing a novel mutation in exon 7 of the EYA1 gene. There was extensive variation of clinical phenotypes within this family. When the physician is confronted with a BOR family showing a wide variation in clinical expression, molecular genetic testing helps to achieve accurate diagnosis. Received: February 23, 1999 / Accepted: April 2, 1999     

Two novel mutations identified in the Wiskott-Aldrich syndrome protein gene cause Wiskott-Aldrich syndrome and thrombocytopenia

Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are rare X-linked genetic disorders caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene. Both disorders are clinically characterized by chronic thrombocytopenia of small platelets. WAS is a more severe form of the disorder and also courses with eczema, and immune dysfunction. In the present study, we investigated two novel mutations of the WASP gene in two Spanish families with patients clinically diagnosed as having XLT and WAS, respectively. In one of the families a missense mutation in exon 12 (1488A>G), resulting in the highly conserved glutamic residue changing to glycine at position 485 (D485G), was identified in several members. Notably, a female of this family, with clinical signs of XLT, was determined as the carrier of the mutation and showed a skewed pattern of X-inactivation, preferentially inactivating the X-chromosome carrying the wild-type allele. In the case of the second family, we describe a WAS patient with a single base deletion in exon 2 (266-267delA), resulting in a frameshift (at codon 78) that creates a stop codon at amino acid 127. As a consequence, there was no WASP expression.     

染色体核型异常与生殖异常的临床研究

目的应用细胞遗传学方法研究染色体核型异常与生殖异常的关系。方法外周血及脐血淋巴细胞培养进行染色体G带分析。结果由于染色体核型异常的不同,出现不同的临床效应。结论在染色体异常核型中,均有不同程度的基因缺失,造成基因连锁的不平衡,因而出现一些临床效应。