X连锁隐性遗传性少汗性外胚层发育不全一家系EDA基因突变分析

目的 对1个X连锁隐性遗传性少汗性外胚层发育不全(X-linked hypohidrotic ectodermal dysplasia,XLHED)家系进行EDA基因检测,分析基因突变类型,探讨其遗传学因素及发病原因.方法 对该XLHED家系进行家系调查,收集家系患者及部分成员和50名无亲缘关系的正常个体的外周血标本并提取基因组DNA,应用聚合酶链反应扩增EDA基因8个外显子,DNA直接测序进行突变检测.结果 该家系中患者检出EDA基因第3外显子存在c.467G＞A突变,导致R156H错义突变.先证者的母亲及姨妈携带c.467G＞A杂合突变,家系中正常个体和正常对照个体均未检测到该突变.结论 EDA基因的R156H突变可能是引起该XLHED家系先证者少汗性外胚层发育不全的致病原因.     

蒙古族牙本质发育不全Ⅱ型一大家系临床分析

目的 探明蒙古族一大家系牙本质发育不全症的临床特点和遗传学基础。方法 采用临床与家系调查相结合的方法对该家系临床特点进行分析。结果 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。该家系患者的临床特点,牙齿X线片等结果显示,发现与已报道的其他民族牙本质发育不全Ⅱ型家系的特点并不完全一致。结论 该蒙古族牙本质发育不全家系属于Ⅱ型,常染色体显性方式遗传。临床表型存在高度的异质性,是否与生活习惯或基因多态性有关有待进一步研究。     

牙本质发育不全Ⅱ型1例家系调查与遗传分析

目的 研究1例遗传性牙本质发育不全Ⅱ型(DGI-Ⅱ)家系致病基因是否与染色体4q21连锁,从分子水平探讨DGI-Ⅱ的发病机制.方法 用FTA洗脱卡对遗传性牙本质发育不全Ⅱ型家系的6名成员进行末梢采血,提取纯化基因组DNA;选择染色体4q21上4个STR标记做荧光标记PCR扩增,分析致病基因与4个STR标记的连锁关系.结...     

一个遗传性脊髓小脑型共济失调大家系的致病基因分析

目的探讨一个遗传性脊髓小脑型共济失调（SCA）大家系的遗传特点和基因突变分析。方法对一个遗传性脊髓小脑型共济失调（SCA）大家系进行家系调查,绘制系谱图,抽取家系成员外周血,采用聚合酶链反应和毛细管电泳对致病基因进行分析检测。结果该家系的遗传性脊髓小脑型共济失调（SCA）为常染色体显性遗传,6代45人中有15人为SCA患者,4人为携带致病基因的无症状患者。患者ATX3基因的CAG三核苷酸重复65-73次。结论该家系为常染色体显性遗传的SCA3型（SCA/MJD）,患者基因突变检测分析显示异常扩增的CAG突变数与发病年龄呈明显的负相关。基因突变检测在疾病诊断和早期发现无症状患者方面有重要作用,从遗传生殖角度阻断该病的遗传有重要意义。     

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.     

一个遗传性痉挛性截瘫家系的全外显子测序分析及产前诊断

目的对一个常染色体显性遗传性痉挛性截瘫(hereditaryspasticparaplegia,HSP)家系进行全基因组外显子测序分析,找出致病的基因突变位点。方法收集一个遗传性痉挛性截瘫家系,提取先证者、先证者父母的DNA进行全外显子组捕获和测序,锁定候选基因致病位点,针对变异位点在该家系6名患者和9名正常人中进行Sanger测序验证,然后通过羊水穿刺和Sanger测序进一步对1例胎儿羊水进行产前诊断。结果该家系中6例病人均在ATL1基因的同一位点处发生突变(c.715CT,p. R239C),家系中9例正常人和1例胎儿羊水中均未发现该突变。结论应用全外显子测序技术对遗传性痉挛性截瘫家系进行诊断,明确致病位点,有助于该家系的遗传咨询和产前诊断。     

一个遗传性牙本质发育不全家系的分子遗传研究

目的 研究一个常染色体显性牙本质发育不全家系发病的遗传基础.方法 通过对一个DSPP家系临床检查和家族史调查,连锁分析和DSPP基因的突变检测,以及限制性片段长度多态分析方法,分析该家系发病的分子基础.结果 连锁分析发现,该疾病致病基因与微卫星标记D4S1534完全连锁,对位于该区域的DSPP基因进行测序分析,发现一个新的致病突变(c.49C→T,p.Pro17Ser),该突变位于DSPP基因的第1外显子.该家系所有患者中都检测到了这一致病突变,但家系中的正常个体和100个无亲缘关系的正常人中未发现这个突变.结论 p.Pro17Ser是牙本质发育不全Ⅱ型致病基因DSPP的一个新的致病突变.我们的研究进一步拓展了对牙本质发育不全疾病分子遗传基础的认识.     

一个遗传性痉挛性截瘫家系的临床特点与spastin基因突变分析

目的探讨遗传性痉挛性截瘫(hereditary spastic paraplegia,HSP)一家系的临床特点及其与spastin基因突变关系。方法对整个家系进行详细的临床检查,先证者和家系内另两例患者进行了肌电图检查,先证者还进行了胸髓核磁共振检查。应用聚合酶链反应结合DNA序列分析方法,检测该家系中先证者和其父亲spastin基因的突变情况。结果家族中所有患者具有遗传性痉挛性截瘫的典型表现,先证者胸髓核磁共振成像显示胸髓明显萎缩,PCR-DNA序列分析患者spastin基因的17个外显子均未发现有异常的突变。结论该HSP家系的患者具有典型的临床表现,并非spastin基因外显子突变所致。     

一个成人多囊肾疾病家系研究分析

目的通过一个家系分析,探讨常染色体显性遗传性多囊肾疾病的病因学、病理学、遗传学因素。方法通过对一个多囊肾家系三代20例家庭成员进行调查,并对六例患者进行B超、肝肾功能检查。结果患者主要表现为双侧肾脏多发性囊肿,部分患者合并肝脏多发性囊肿,多于35岁以后起病,伴有腹胀,高血压,血尿等症状,部分患者行囊肿去顶开窗手术,有一例患者合并多囊脾。家系遗传分析表明该疾病属于常染色体显性遗传性多囊肾疾病,其中多囊肝为肾外表现。结论本病发病机制与基因缺陷相关,尤其是PKD1、多囊蛋白-1、PKD2、多囊蛋白-2、PKD3等,家系中如果亲代发病,子代中亦会有发病,年龄在35岁以后为多。     

先天性外胚层发育不全无汗综合征家系报告及文献复习

目的通过一个家系分析,探讨先天性外胚层发育不全疾病的遗传方式。方法现场对一个无汗先天性外胚层发育不全家系四代27例家庭成员进行调查,并对1例患者进行医学分析。结果患者主要表现为头发稀疏,无牙,无体毛,无汗等症状。家系遗传分析表明该疾病属于X连锁隐性遗传疾病。结论本病发病机制与X染色体上的基因缺陷有关,如ED1、NEMO等,据此可开展进一步基因突变检测。     

A rare case of hemochromatosis and Wilson's disease coexisting in the same patient

Wilson's disease and hereditary hemochromatosis are two inherited diseases with life-threatening complications. Early recognition and prompt treatment may be instrumental in reducing such complications associated with these disorders. Although both Wilson's disease and hereditary hemochromatosis are genetic in nature, the two conditions have distinct, unrelated genetic etiologies. Two distinct, separate mutations are required for simultaneous existence of the two diseases. As such, the likelihood of the two conditions coexisting is exceedingly rare. Here we report a case of a 23-year-old male with hereditary hemochromatosis with coexistent Wilson's disease. Only two reported cases exist in which this dual diagnosis was present simultaneously. In our patient, laboratory evaluation demonstrated elevated ferritin, transferrin saturation >90%, and subsequent liver biopsy demonstrated diffuse fibrotic changes. Confirmatory genetic analysis revealed the patient to be a compound heterozygous for C282Y and H63D gene mutations. Given the patient's young age and the improbability of hemochromatosis-induced hepatic damage at that age, an alternative diagnosis was sought. Further analysis revealed reduced serum ceruloplasmin along with elevated urinary copper excretion. Subsequent ophthalmologic exam revealed bilateral Kaiser Fleischer rings. In conclusion, Wilson's disease and genetic hemochromatosis both involve inherent flaws in the transportation of heavy metals and their accumulation in hepatocytes. Although both diseases arise from distinctly different genetic mutations, the coincidence of the two disorders can, in rare cases, occur.     

What is in a cause? Exploring the relationship between genetic cause and felt stigma

PURPOSE: Concern over stigma as a consequence of genetic testing has grown in response to the recent increase in genetic research and testing resulting from the Human Genome Project. However, whether a genetic or hereditary basis necessarily confers a stigma to a condition remains unexamined. METHODS: We performed a qualitative interview study with 86 individuals with one of four conditions: deafness or hearing loss, breast cancer, sickle cell disease, and cystic fibrosis. The first two groups were divided approximately between people who ascribed their conditions to a genetic or hereditary cause and those who did not. RESULTS: Respondents interpreted genetic or hereditary causes and nongenetic causes in a variety of ways. Subjects with breast cancer reported the most consistently negative interpretation of genetic cause. This response concerned future ill health, not an enduring sense of stigma. Deaf and hard of hearing subjects provided the most consistently positive comments about a genetic or hereditary basis to their condition, casting familial hearing loss as a vital component of group and individual identity. Respondents with sickle cell disease and cystic fibrosis offered similar and positive interpretations of the genetic cause of their condition insofar as it meant their conditions were not contagious. CONCLUSIONS: Although some subjects report feeling stigmatized as a result of their condition, this stigmatization is not uniformly associated with the condition's cause, genetic or otherwise. Instead, stigma emerges from a variety of sources in the context of the lived experience of a particular condition.     

陕北地区临床遗传病调查研究

本文对陕北地区一个地区级医院、六个县级医院从１９８１～１９９０年十年间临床所见的遗传病作了调查分析。共查阅病历１８８，９４３份，其中遗传病２３，４１８份，占总病历数的１２．３９％；男性遗传病１３，８００例，女性９．１８１例，男：女＝１．５：１。以发病年龄看，婴幼儿多于青少年，青少年多于中老年；按年度计算，前５年明显少于后５年。共发现遗传病种类１３１种，其中单基因病６７种、３５６３例，占遗传病例１５．２１％；多基因病４８种，１８４８２例，占遗传病例７８．９２％；染色体病１６种，１３７３例，占遗传病例５．８６％。从本资料可见，多基因病最多，而且随年度出现率增高。其次隐性遗传病和染色体病较多，这可能与陕北地区自然条件差和科学文化发展慢以及通婚圈小等有关。     

An atomic force microscopic study of the ultrastructure of dental enamel afflicted with amelogenesis imperfecta

The ultrastructure of human tooth enamel from a patient diagnosed to have amelogenesis imperfecta (AI) was investigated using atomic force microscopy (AFM) and compared with normal human tooth enamel. AI is a hereditary defect of dental enamel in which the enamel is deficient in either quality or quantity. Tissue-specific proteins, especially amelogenins, have been postulated to play a central role in amelogenesis. The secondary structure of amelogenin has been assigned an important role in directing the architecture of hydroxyapatite (HA) enamel crystallites and an alteration of the secondary structure of amelogenin is expected to result in an altered architecture of the mineral phase in human enamel. Previous studies have shown that the human amelogenin gene encodes for a mutant protein in which a conserved Pro is mutated to a Thr residue (Pro → Thr); such a mutation should be expected to cause a disoriented pattern of the mineral phase in enamel. AFM results presented for the AI tooth enamel clearly demonstrate that the apatite crystal morphology in AI tooth enamel is perturbed in the diseased state; this might result from a defective synthesis of the extracellular matrix proteins, e.g. amelogenin, by the ameloblasts.     

An atomic force microscopic study of the ultrastructure of dental enamel afflicted with amelogenesis imperfecta

The ultrastructure of human tooth enamel from a patient diagnosed to have amelogenesis imperfecta (AI) was investigated using atomic force microscopy (AFM) and compared with normal human tooth enamel. AI is a hereditary defect of dental enamel in which the enamel is deficient in either quality or quantity. Tissue-specific proteins, especially amelogenins, have been postulated to play a central role in amelogenesis. The secondary structure of amelogenin has been assigned an important role in directing the architecture of hydroxyapatite (HA) enamel crystallites and an alteration of the secondary structure of amelogenin is expected to result in an altered architecture of the mineral phase in human enamel. Previous studies have shown that the human amelogenin gene encodes for a mutant protein in which a conserved Pro is mutated to a Thr residue (Pro-->Thr); such a mutation should be expected to cause a disoriented pattern of the mineral phase in enamel. AFM results presented for the AI tooth enamel clearly demonstrate that the apatite crystal morphology in AI tooth enamel is perturbed in the diseased state; this might result from a defective synthesis of the extracellular matrix proteins, e.g. amelogenin, by the ameloblasts.     

In vivo confocal microscopy analysis of enamel defects after orthodontic treatment: A preliminary study

After orthodontic treatment with fixed appliances, bonded brackets and residual adhesive must be removed. This procedure should lead to restitutio ad integrum of the enamel or, at least, restore the enamel surface as closely as possible to its pre-treatment conditions. The purpose of this study is the in vivo assessment at a microscopic resolution of enamel surfaces after bracket debonding while avoiding the tooth extraction. Nine orthodontic patients who had brackets removed at the conclusion of orthodontic treatment were enrolled. In vivo reflectance confocal microscopy imaging of dental enamel surface after debonding was performed for each patient. Eighteen upper incisors were analyzed, 10 in which the enamel demineralization appeared after the treatment and 8 in which the demineralization was present before the treatment. RCM analyses showed some speckled or roundish dark areas within the enamel. Moreover enamel alterations were detected at different levels of depth. The present in vivo microscopic study allowed for highlighting structural features in dental enamel, after debonding, at a microscopic resolution in real-time and in a non-invasive way, without the need for extraction or processing of the samples.     

Mendelian diseases and conditions in Croatian island populations: historic records and new insights

Among Croatian islands, there are several which are known for unusual autochthonous diseases and specific medical conditions that result from the reproductive isolation and specific population genetic structure. These populations are characterized by high degree of genetic isolation, consanguinity, and inbreeding. The reported diseases include Mal de Meleda on Mljet island, hereditary dwarfism on Krk island, familial learning disability on Susak island, familial ovarian cancer on Lastovo island, and several other rare diseases and conditions inherited in Mendelian fashion. We present a historical perspective on how these conditions were first described, interpreted, and assessed. We reviewed the information obtained through genetic research in the past several years, when the genetic etiology of some of these conditions was explained. The disease gene causing Mal de Meleda was first localized at 8q chromosome, and mutations in the ARS (component B) gene encoding SLURP-1 (secreted mammalian Ly-6/uPAR-related protein 1) protein were identified subsequently. The genetic etiology of dwarfism on the island of Krk is explained by a mutation in the PROP1 gene, responsible for the short stature. The search for mutations underlying other monogenic diseases in Croatian islands is under way.     

Exclusion mapping of the hereditary dentatorubropallidoluysian atrophy gene from the Huntington''s disease locus.

Hereditary dentatorubropallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder. Clinical and genetic findings in hereditary DRPLA are very similar to those of Huntington's disease (HD). However, it can be differentiated from HD by the pathological findings of dentatorubral and pallidoluysian atrophies and by a lack of prominent atrophy of the striatum at necropsy. The hereditary DRPLA gene has not been localised and the possibility that the two disease loci are allelic has been suggested. We have searched for linkage between the locus for hereditary DRPLA and D4S10 using the G8 probe, which is a genetic marker linked to HD. In four families, there were negative scores at all recombination fractions and the lod score was -2.215 at recombination fraction theta = 0.15. These data indicate that the locus for hereditary DRPLA is not closely linked to D4S10 and that hereditary DRPLA is a distinct disease from HD.     

Hereditary Tumor Syndromes of the Nervous System: Overview and Rare Syndromes

Hereditary tumor syndromes of the nervous system are a varied group of conditions that include neurofibromatosis 1, neurofibromatosis 2, tuberous sclerosis, and von Hippel-Lindau disease, as well as the retinoblastoma susceptibility, Li-Fraumeni, familial glioma, Turcot, Gorlin, Cowden and multiple endocrine neoplasia syndromes. For many of these conditions, the responsible genes have been localized or identified. Such studies have elucidated the genetic basis of both hereditary cancer predisposition and sporadic nervous system tumors. The first four hereditary tumor syndromes have been extensively studied and are discussed in detail in the four subsequent articles. The other syndromes have also been subject to both pathological and molecular genetic inquiries. In this introductory overview, we discuss the features common to the hereditary tumor syndromes of the nervous system, and review some of the rarer conditions.