河南省致死性家族性失眠症家系的流行病学调查及遗传规律研究

目的 调查致死性家族性失眠症(FFI)家系谱特征及家族发病史;分析病例的临床特点和病理学改变;研究FFI家系的流行病学特征及相关基因遗传规律.方法 通过7代135名家族成员的流行病学调查,了解家族史、家族迁徙史及发病史;对患者及部分家族成员抽取静脉血进行PRNP基因PCR扩增,序列测定和Nsp I酶切鉴定;尸检采集脑组织进行神经病理学检测和Western blot法PrPCc蛋白检测.结果 2例确诊患者临床症状典型;11名家族成员死于相似的神经性疾病;32名家族成员血标本检测,其中11人出现PRNP基因178位密码子点突变(D178N),突变检出率34.38%,第129位密码子为甲硫氨酸;病例脑组织海绵样变性和神经元缺失,可检测到PrPSc蛋白.结论 该家系为FFI家系,病例临床症状典型,病理特征明显.流行病学调查、基因特征分析、神经病理学和Westernblot法检测对确立FFI病例和家系有至关重要的作用.     

两种错义突变p.Glu502Lys和p.Gly542Ser所致遗传性Ⅻ缺陷症家系的分析

目的对1个近亲结婚的遗传性凝血因子Ⅻ(FⅫ)缺陷症家系进行凝血指标检测和基因突变分析,探讨其分子发病机制。方法检测先证者及其家系成员血浆凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、FⅫ活性(FⅫ:C)等凝血指标;对先证者FⅫ基因所有的外显子及其侧翼序列进行PCR扩增和DNA直接测序。针对先证者的突变位点,对该家系成员进行相应的基因突变检测。结果先证者和其妹妹APTT、FⅫ:C明显异常,分别为174.8 s、0.8%和109.5 s、1.9%。基因测序发现先证者和其妹妹FⅫ基因存在13号外显子c.1561G>A(p.Glu502Lys)及14号外显子c.1681 G>A(p.Gly542Ser)2种杂合错义突变。家系分析表明先证者父亲和儿子携带c.1561G>A杂合突变,母亲携带c.1681 G>A杂合突变。先证者及家系成员FⅫ基因第1外显子启动子区46位多态性均为46C>T型。结论 FⅫ基因p.Glu502Lys和p.Gly542Ser 2种杂合错义突变是导致先证者遗传性FⅫ缺陷症的分子发病机制。     

糖原累积病Ⅳ型1例及其家系的临床和分子遗传分析

目的 研究1例糖原累积病Ⅳ型(GSD Ⅳ)患者及其家系的基因突变情况。方法 患儿,女,1岁5个月,因轻度黄疸,肝脾肿大2月,生长迟缓1年就诊。采集该家系先证者及其父母,两个哥哥的外周血,采用二代测序方法查找先证者致病基因及突变位点,Sanger测序进行突变验证。结果 该家系先证者为GBE1基因c.1571G>A纯合错义突变,双亲及一个哥哥为GBE1基因c.1571G>A杂合错义突变,另一个哥哥基因检测未见该突变,确诊为GSD Ⅳ型,建议行肝移植治疗,因家属拒绝,患儿于生后22个月死亡。结论 首次在国内报道了GSD Ⅳ型的家系及其分子遗传情况以及GBE1基因c.1571G>A纯合突变,丰富了GSD Ⅳ型在中国人群的突变谱。     

全外显子组测序鉴定侏儒症家系基因突变及产前诊断

目的 揭示一侏儒症患者家系的遗传病因,为遗传咨询和产前诊断提供有效信息。方法 应用全外显子组测序(whole exome sequencing, WES)技术对侏儒症家系成员进行致病基因及突变位点筛查,结合临床表型,确定候选基因的致病位点,通过Sanger测序法对WES结果进行验证,排除二代测序假阳性位点。最后,利用鉴定得出的该家系致病基因的突变位点信息对患者胎儿进行产前诊断。结果 WES结果显示先证者、先证者父亲、先证者胎儿均存在FGFR3基因NM＿001163213.1:c.1626C>G(p.Asn542Lys)位点杂合变异,先证者妻子此未位点未发生突变。胎儿经超声检测股骨长度低于-2SD,有极大概率患有侏儒症。Sanger测序检测结果与上述WES结果一致,进一步证明了该检测结果的可靠性。结论 FGFR3基因NM＿001163213.1:c.1626C>G(p.Asn542Lys)位点杂合变异是侏儒症的重要发病原因,侏儒症患者3代的遗传咨询和产前诊断应重视该位点的检测。     

罕见β-地贫-88 C>G( HBB： c.-138 C>G)杂合突变复合ɑ-地贫家系一例的分子遗传学特征并文献复习

为探讨1例罕见β-地贫基因-88 C>G(HBB:c.-138 C>G)杂合突变(β-88 C>G/βN)复合α-地贫基因Hb Westmead杂合突变(ɑwsɑ/ɑɑ)家系的分子遗传学特征。上海儿童医学中心三亚市妇女儿童医院产前诊断中心于2022年6至8月对该家系三代成员进行队列研究, 采集该家系三代成员的外周血样本进行血常规、血红蛋白(Hb)分析, 采用二代测序技术(NGS)对家系成员的外周血样本进行地中海贫血基因检测, 并采用Sanger测序进行验证。结果显示, 该家系成员中先证者、先证者父亲、先证者叔叔及先证者堂弟平均红细胞体积(MCV)分别为70.1 fl、71.9 fl、73.1 fl 以及76.6 fl, 平均红细胞血红蛋白量(MCH)分别为21.5 pg、22.0 pg、22.6 pg以及 23.5 pg, 血红蛋白A2(HbA2)分别为5.3%、5.4%、5.4%以及5.5%, 均表现为小细胞低色素、HbA2值升高, 胎儿血红蛋白(Hb F)略升高或正常, 无贫血;先证者祖母、母亲及弟弟的分析结果均正常。基因分析结果示:先证者携带β-88 C>...     

先天性白内障家系的产前超声与致病基因研究

目的分析先天性白内障家系的产前超声诊断情况和致病基因,为发现潜在基因突变位点和早诊早治提供科学依据。方法对1例先天性白内障先证者孕妇进行产前超声检查和病史调查,在其分娩后采集双胎脐血。经过完善的眼科学检查后,采集该大家系共19名成员(包括10名患者,9名非患者)血液样品,将患者与非患者进行全外显子组基因测序,筛选候选基因,对基因突变位点进行直接测序并在相关群体中进行验证。结果产前超声检查发现该患者分娩双胎均为先天性白内障患者,该家系为5代患病的先天性白内障常染色体显性遗传家族。经全外显子基因组测序,新发现SNP 2 553个,新发现Indel 3881个。经候选基因一代测序,验证发现家系内患者CRYGD基因第2外显子70位有1个CA碱基的杂合突变(c.70CA),并由此导致了蛋白第24位上脯氨酸被苏氨酸所取代(p.Pro24Thr),正常对照未见该点突变。结论 CRYGD基因的错义突变c.70CA是该先天性白内障家系的致病原因。家系调查询问病史尤为重要,在孕期错过基因诊断的情况下,产前超声诊断为更有效的筛查手段。     

应用分子遗传学方法进行Wilson病的症状前诊断

目的 采用分子遗传学的方法，为Wilson病（WD）家系中症状前期WD患者明确诊断。方法 采用与Wilson病致病基因紧密连锁的遗传标记。构建染色体单体型。分析先证者与待诊者的异同；检测待诊者是否存在与先证者相同的致病突变，寻找症状前期患者。结果 在10个WD家系中找到了2例症状前期的WD患者其中一例为仅1个月的婴儿；同时为一例血清铜蓝蛋白低于正常的携带者明确了诊断。结论 采用染色体单体型分析结合突变检测的方法，能为WD家系中症状前期病人明确诊断，使之得到及时的治疗。     

耳聋基因诊断技术作为新生儿听力筛查补充手段的应用价值

目的探索耳聋基因诊断技术作为新生儿听力筛查补充手段的应用价值,旨在为新生儿遗传性耳聋病例及其家系提供更科学的再发风险和再生育指导。方法收集2013-2016年温州市鹿城、瑞安、永嘉3个地区经新生儿听力筛查发现、确诊的耳聋病例,从中筛选疑似为遗传性耳聋的29例先证者及其家庭成员77名共同纳入研究,采集病史及家族史、结合听力及影像学检查,提取家系先证者及其家系成员的外周血基因组DNA,对GJB2、SLC26A4和12S rRNA基因的扩增产物进行DNA测序,并进一步对基因序列变异进行生物信息学分析和对比。结果共检出17个耳聋儿家庭携带常见耳聋致病基因突变,2例先证者及其父母均为GJB2纯合突变导致的遗传性耳聋,患儿父母再生育耳聋儿风险为100.00%。4例先证者为GJB2纯合突变导致的遗传性耳聋,其父母均为GJB2突变携带者;1例先证者为SLC26A4纯合突变导致的大前庭水管综合征,其父母均为SLC26A4突变携带者,2例先证者为GJB2 V371(c.109GA)纯合突变,该位点突变更倾向于致病突变;以上7个耳聋家族患儿父母再生育耳聋儿风险为25.00%。结论耳聋基因诊断技术作为听力筛查后续补充手段有利于明确新生儿疑似遗传性耳聋患儿的遗传病因,能科学客观地为患儿及其家系提供再发风险和再生育咨询与指导。     

2个范德伍德综合征家系的IRF6基因突变检测

目的对2个中国范德伍德综合征(Van der Woude syndrome,VWS)家系进行临床和遗传特点分析,并进行IRF6基因的突变检测,明确中国人VWS致病基因IRF6的突变情况,并发现可疑的突变热点区域。方法通过先证者及现场家系调查、临床检查和系谱分析收集2个VWS家系成员24人的外周血样本,提取DNA用于IRF6基因的聚合酶链扩增反应(polymerase chain reaction,PCR)。采用Sanger测序法对所有VWS家系成员的IRF6基因的编码区7个外显子进行测序,使用mutation surveyor软件对测序结果与参考序列进行比对分析。结果 2个家系24人中受累患者6名,5名(83.3%)患者有唇腭裂,5名(83.3%)患者有唇瘘,6名患者均无牙齿发育不全表现,唇瘘伴唇腭裂表型常见,无其他组织器官畸形。24名成员均进行了IRF6基因第3至第9外显子的测序,6名患者均存在基因突变,家系1的3名患者均携带位于第9外显子的c.1234CT杂合突变;家系2的3名患者均携带位于第9外显子的c.1210GA杂合突变;未发现其他非患者的家系成员携带IRF6基因突变。结论 VWS综合征存在遗传异质性和临床表型复杂性,患者的表型与致病突变有关。通过基因检测可以对VWS患者进行遗传分析和产前诊断,弥补产前超声容易漏诊的不足。     

ATRX新致病性变异致X连锁智力低下家系分析

目的：分析一个α地中海贫血X连锁智力障碍(ATR-X)综合征家系的致病基因突变。方法：对该ATR-X综合征家系先证者进行全外显子组测序,通过生物信息学分析筛选候选的致病基因突变位点,利用聚合酶链反应(PCR)和Sanger测序验证该家族成员的致病突变位点。结果：全外显子组测序发现先证者的X染色体ATRX基因存在半合子变异(c.161₁62del, p.Ser54Ter),家系成员Sanger测序结果表明该变异在家系中符合遗传共分离规律。结论：ATRX基因c.161₁62del变异为引起该家系ATR-X综合征的遗传学因素。     

Clinical,histopathological and genetic studies in a family with fatal familial insomnia

We compared clinical data from two related Chinese patients with fatal familial insomnia (FFI) and collected information about their pedigree. The clinical features in the two cases were similar and included initial progressive insomnia and sympathetic activation, which persisted throughout the clinical course. A total of 135 members of this family, across seven generations, were retrospectively investigated. Eleven family members, including the two FFI cases, were found to have died with similar neurological problems. Analysis of PRNP in 32 family members revealed eleven carrying the D178N allele, including the two FFI patients. Spongiform degeneration in brains was not found, but gliosis was obvious in the thalamus of the two cases at postmortem. Proteinase K-resistant prion protein (PrP) was not found in proband's brain by immunohistochemistry, but observed in some areas of brain for both cases by PrP-specific Western blot. Investigation of the pedigree has led to the identification of an additional 9 family members who had similar clinical symptoms and 9 currently healthy individuals with the D178N mutation.     

成都市献血员HCV感染的家庭聚集性研究

目的　分析丙肝病毒(HCV)感染存在家庭聚集现象,以及在排除影响因素的混杂效应下,HCV感染存在家庭聚集现象的可能性。方法　在成都市血液中心收集1997- 10 / 1998- 10献血员名单,采取分层整群抽样方法确定献血员,应用分层分析研究混杂效应。结果　抗-HCV阳性献血员的家庭成员的抗-HCV阳性率(18 .4 9% )高于抗-HCV阴性献血员的家庭成员(7 4 .2 % )。在排除家庭成员的献血史、家庭外丙肝接触史的混杂效应下,家庭内丙肝接触史与HCV家庭聚集有关,有家庭内接触丙肝史者感染HCV的危险更大。结论　研究结果提示HCV在家庭内的传播可能有夫妇间、母亲与子女、父亲与子女及其他方式。     

Familial hypercholesterolaemia and quality of life in family members

BACKGROUND: Awareness of genetic disease in the family may influence quality of life. The purpose of this study was to describe quality of life among nonaffected members of families with familial hypercholesterolaemia. All were aware of the risk for coronary heart disease. Their quality of life was compared with a reference group and with the patients with familial hypercholesterolaemia themselves. METHODS: Names of family members (n = 129) were given by the patients with familial hypercholesterolaemia. A randomly selected reference group (n = 1485) and patients with familial hypercholesterolaemia (n = 185) were included for comparison. They all completed the questionnaire Quality of Life Index, the Hospital Anxiety and Depression Scale, and the Mastery Scale measuring coping. Family members and patients with familial hypercholesterolaemia also completed a questionnaire on health and lipids. RESULTS: Family members were more satisfied with family life, mean 22.1 +/- 3.5 (SD), and psychological/spiritual life, 22.9 +/- 4.0, than the reference group, 21.4 +/- 4.3 and 21.1 +/- 4.8, respectively; this was particularly expressed among partners, P < 0.05. Of family members, 91% were anxious about the patient with familial hypercholesterolaemia developing coronary heart disease. CONCLUSIONS: Family members have as good a quality of life as members of the reference group, but they were anxious about the patient with familial hypercholesterolaemia developing coronary heart disease.     

Familial aggregation of oesophageal cancer in Yangcheng County, Shanxi Province, China.

Oesophageal cancer is the second most common cause of cancer death in China and is particularly prevalent in northern China. Genetic factors have been studied less than environmental factors in the aetiology of this disease. This study was conducted to evaluate familial aggregation of oesophageal cancer. All households in Yangcheng County were interviewed in 1979 to determine family history of oesophageal cancer. In 1989, vital status for all family members from three Yangcheng villages was determined and re-interviews were conducted among families who reported a positive family history of oesophageal cancer in 1979. Risk of oesophageal cancer was evaluated by comparing family and individual rates of oesophageal cancer during the 1979-1989 interval stratified by the number of family members with oesophageal cancer prior to 1979. More families with prior oesophageal cancer history reported new oesophageal cancer deaths during the follow-up period than families without prior history (19% versus 5%). Oesophageal cancer rates increased with increasing positivity of family history, and adjustment for other risk factors did not substantially alter this result. We conclude that these data provide evidence for familial aggregation of oesophageal cancer.     

Von Hippel-Lindau disease: protocols for diagnosis and periodical clinical monitoring. National Von Hippel-Lindau Disease Working Group

Von Hippel-Lindau disease (VHL) is an autosomal dominantly inherited syndrome with high penetrance, characterised by tumours in various organs. The Dutch VHL working group presents guidelines for DNA testing and clinical monitoring, to enhance early detection and treatment of VHL patients in the Netherlands. Diagnosis of VHL is justified in patients presenting with a typical VHL tumour with a positive family history, but patients with a VHL tumour and a negative family history may also have VHL. Diagnosis of VHL can be confirmed by molecular genetic analysis of the VHL gene which is informative in virtually all VHL families. In a patient with (suspicion for) VHL there is an indication for genetic counselling. A protocol for clinical monitoring of VHL is presented and is recommended for: carriers of a VHL germline mutation; members of VHL families with an unknown familial mutation; members of VHL families who decline testing of the familial mutation; patients suspected for VHL, but without a detectable VHL gene mutation.     

Family-centered approaches to understanding and preventing coronary heart disease

Family history represents the contributions and interactions of unique genomic and ecologic factors that affect the metabolic profile and life course of a family and its members. It is well known that a family history of coronary heart disease (CHD) is a significant predictor of an individual's risk for CHD even after adjusting for an individual's own established risk factors, such as hypertension, smoking, and abnormal lipoprotein levels. The explanation for the observed familial disease aggregation is not well understood except for the general knowledge that genetic and environmental factors predisposing to CHD also aggregate in families. Given the multifactorial nature of an individual's risk, it can be argued that an individual's familial risk of disease may, in fact, be a better indicator of the many complex interactions among predisposing genetic and environmental factors than can be captured by an individual's own risk factors. Issues of how to assess, quantitate, and apply family history information in clinical settings still need to be resolved. Some clinical risk indicators, such as the National Cholesterol Education Program III guidelines, take into account family history, while others, such as the Framingham Risk Score, do not. Moreover, several family-centered intervention studies have demonstrated the particular advantages of focusing on families rather than just individuals. Although there has been tremendous progress in primary prevention of CHD over the last 20 years, substantial advancements may still be achieved by focusing on the family as its own unit of inference and as a specific target for disease prevention.     

广西壮族人群肝癌家族聚集与细胞色素P450 2E1基因多态性等因素关系的研究

目的 探讨广西壮族人群肝癌高发家族聚集与细胞色素P450 2E1(CYP2E1)基因多态性等因素的关系.方法 在广西某肝癌高发现场壮族人群中,对10个肝癌高发家族成员(共91名)和10个无癌对照家族成员(共102名).采集外周血标本,以多聚酶链反应-限制性片段长度多态性技术(PCR-RFLP).分析所有研究对象CYP2EI基因Rsa I位点基闪型及等位基因的分布频率;并用ELISA法检测HBsAg.肝癌相关因素的暴露情况则应用统一问卷进行调查.结果 肝癌高发家族成员CYP2EI基因Rsa I位点c1/c1、c1/c2基因型频率分别为63.7%和36.3%;在对照家族成员中,相应的频率分别为48.0%和52.O%(OR=1.901,95%CI:1.067～3.387);两组成员Rsa I位点基因型分布的差异有统计学意义(X2=4.797,P=0.029).非条件logistic回归分析结果显示,当地肝癌家族聚集的主要危险因素,按其危险度由高至低排列依次为:以玉米为主食、HBsAg携带、CYP2E1 c1/c1型.结论 在广西壮族人群中,肝癌的家族聚集与家族成员的CYP2E1基因Rsa I多态性的分布,有肯定的统计学关系;CYP2E1基因Rsa I多态性的分布不是引起肝癌家族聚集的惟一因素,也不是首要因素,与其他一些因素的综合作用更为重要.     

广西壮族人群肝癌家族聚集与细胞色素基因多态性等因素关系的研究

探讨广西壮族人群肝癌高发家族聚集与细胞色素P4502E1(CYP2E1)基因多态性等因素的关系。方法在广西某肝癌高发现场壮族人群中,对10个肝癌高发家族成员(共91名)和10个无癌对照家族成员(共102名)。     

Health family trees: a tool for finding and helping young family members of coronary and cancer prone pedigrees in Texas and Utah.

We report on the feasibility and utility of a new approach for identifying the small percentage of families in the general population with strong familial predisposition to early coronary heart disease, strokes, and common familial cancers (breast, colon, lung), using the "Health Family Tree," a medical family history. A total of 24,332 "trees" were completed by parents and students in 37 high schools in 14 urban and rural communities in Texas and Utah during the years 1980-86. Completed "trees" were obtained from 68 per cent of all enrolled students. High-risk families, included 1,796 families with early coronary disease (7.5 per cent of all student families or 3.7 per cent of their parents' families), 870 stroke families (3.6 per cent), and 415 cancer prone families (1.7 per cent). Among these 3,081 high-risk families there were 8,245 family members already reported to have been diagnosed by a physician to have the familial disease of interest and 43,269 high risk unaffected siblings and offspring of these persons. The average cost per identified high-risk unaffected person was under $10. We conclude that the "Health Family Tree" is a feasible and cost-effective way to find high-risk families.