Adult polycystic kidney disease: knowledge, experience, and attitudes to prenatal diagnosis.

One hundred and ninety subjects from 100 adult polycystic kidney disease (APKD) families on the North Western Regional Genetic Register were interviewed to determine the likely demand for prenatal diagnosis. A detailed questionnaire was used to assess understanding and experience of clinical, therapeutic, and genetic aspects of APKD. Major features of the disease (presence of renal cysts which can lead to renal failure) and forms of therapy (dialysis and transplantation) were known; knowledge of less common features was related to experience. The cohort had had genetic counselling and the majority knew the risk to their own offspring, although the mechanics of the mode of inheritance was often misunderstood. Uptake of presymptomatic ultrasound testing was high, and some implications of early diagnosis are noted. A minority changed their reproductive behaviour as a result of APKD, and although the majority felt a prenatal test should be available, only 23% at high risk of passing on the disease and contemplating children felt they would be interested, and so far only one request for prenatal diagnosis has been received. Thus, demand appears to be low and to be related to perception of the seriousness of APKD.     

Non‐invasive prenatal diagnosis for single gene disorders: experience of patients

The aim of this study is to explore women's experiences of using newly developed non‐invasive prenatal diagnosis (NIPD) for single gene disorders. Methods used in this study include qualitative one‐to‐one interviews with eight women with pregnancies at risk of achondroplasia, Apert syndrome, thanatophoric dysplasia or a neuromuscular condition. The results of the study show that the women were positive about an accurate, safe, and early test. Where the foetus was at increased risk of inheriting a genetic condition, the benefits of NIPD over invasive testing were that it reduced the period of uncertainty and worry by being conducted within the first trimester. For those women for whom there was a low recurrence risk, the period of uncertainty could be reduced and pregnancy ‘normalized’ earlier. For women who would not have risked invasive testing, NIPD enabled them to have an early diagnostic test that was more accurate than ultrasound. Where ultrasound abnormalities were detected, NIPD ended the ‘diagnostic odyssey’, enabling women to make practical and psychological preparations for the birth. NIPD conducted through specialist services was considered most appropriate. NIPD for these particular single gene disorders was appreciated by women and appears to be satisfactory. Further exploration of stakeholder views may be required to inform more widespread implementation of NIPD for a broader range of genetic conditions.     

利用母血胎儿游离DNA进行单基因病无创产前诊断研究进展

母血中胎儿游离DNA的发现为单基因遗传病的无创产前诊断提供了新途径.过去10年来,相继发展了多种技术(实时荧光PCR技术、焦磷酸解激活的聚合反应技术、质谱技术、数码PCR技术)用于母血胎儿游离DNA的检测,推动了单基因遗传病无创产前诊断研究的发展.现将相关技术的基本原理、存在优缺点等方面作一综述,以期对单基因遗传病无创产前诊断的发展有所帮助.     

Detection of sickle gene by coelocentesis in early pregnancy: a new approach to prenatal diagnosis of single gene disorders

Coelomic fluid, placental tissue and maternal blood were collectedat 7–10 weeks gestation from each of 58 women undergoingelective termination of pregnancy for psychological indications.In all samples, a 364 bp fragment of the human ß-globingene spanning positions -23 to 341 was amplified. The restrictionendonuclease Ddel was used to detect the sickle mutation whichabolishes its restriction she. ß-Globin DNA was successfullyamplified from all samples. In 53 cases a normal maternal ß-globingenotype was detected. In three out of five cases, where thematernal haemoglobin phenotype was HbAS, heterozygosrty forthe sickle mutation was demonstrated on analysis of coelomicfluid. In the remaining two cases a normal ß-globingenotype was observed. Three further coelomic fluid sampleswere found to be heterozygous for the sickle mutation. In theseinstances the maternal haemoglobin phenotype was normal, indicatingpaternal transmission of the sickle gene. The results of thepresent study have established that the diagnosis of sicklecell anaemia, and potentially other human single gene disorders,is feasible by coelocentesis. coelocentesis/early pregnancy/prenatal diagnosis/sickle cell disease     

Cystic fibrosis: community knowledge and attitudes towards carrier screening and prenatal diagnosis

The rate of technical advance in genetics contrasts sharply with the slow diffusion of information on this subject to the general population. In this paper, we investigate the initial knowledge about cystic fibrosis of a group of adults with increased interest in psychosocial issues, but with no special pre-existing knowledge or training in genetics. Attitudes towards carrier screening and prenatal diagnosis for CF were also evaluated, after brief written information had been given on this disease. We found that the studied group had only a poor knowledge of the nature of CF and an even more limited awareness of its inheritance. This knowledge was mainly associated with educational level. Most respondents had no objections to population-wide carrier screening for CF, at least if the test was proposed and not systematically imposed by the government. It is striking that a smaller proportion were interested in knowing their own carrier status. The majority of the group were in favour of prenatal diagnosis for CF. Factors associated with knowledge and attitudes are described. In the discussion, special attention is paid to the psychosocial complexity of mass screening.     

Non-invasive prenatal testing for single gene disorders: exploring the ethics

Non-invasive prenatal testing for single gene disorders is now clearly on the horizon. This new technology offers obvious clinical benefits such as safe testing early in pregnancy. Before widespread implementation, it is important to consider the possible ethical implications. Four hypothetical scenarios are presented that highlight how ethical ideals of respect for autonomy, privacy and fairness may come into play when offering non-invasive prenatal testing for single gene disorders. The first scenario illustrates the moral case for using these tests for ‘information only'', identifying a potential conflict between larger numbers of women seeking the benefits of the test and the wider social impact of funding tests that do not offer immediate clinical benefit. The second scenario shows how the simplicity and safety of non-invasive prenatal testing could lead to more autonomous decision-making and, conversely, how this could also lead to increased pressure on women to take up testing. In the third scenario we show how, unless strong safeguards are put in place, offering non-invasive prenatal testing could be subject to routinisation with informed consent undermined and that woman who are newly diagnosed as carriers may be particularly vulnerable. The final scenario introduces the possibility of a conflict of the moral rights of a woman and her partner through testing for single gene disorders. This analysis informs our understanding of the potential impacts of non-invasive prenatal testing for single gene disorders on clinical practice and has implications for future policy and guidelines for prenatal care.     

Diagnosing and preventing inherited disease: Detection of sickle gene by coelocentesis in early pregnancy: a new approach to prenatal diagnosis of single gene disorders

Coelomic fluid, placental tissue and maternal blood were collectedat 7–10 weeks gestation from each of 58 women undergoingelective termination of pregnancy for psychological indications.In all samples, a 364 bp fragment of the human -globin genespanning positions –23 to 341 was amplified. The restrictionendonuclease Ddel was used to detect the sickle mutation whichabolishes its restriction site. -Globin DNA was successfullyamplified from all samples. In 53 cases a normal maternal -globingenotype was detected. In three out of five cases, where thematernal haemoglobin phenotype was HbAS, heterozygosity forthe sickle mutation was demonstrated on analysis of coelomicfluid. In the remaining two cases a normal -globin genotypewas observed. Three further coelomic fluid samples were foundto be heterozygous for the sickle mutation. In these instancesthe maternal haemoglobin phenotype was normal, indicating paternaltransmission of the sickle gene. The results of the presentstudy have established that the diagnosis of sickle cell anaemia,and potentially other human single gene disorders, is feasibleby coelocentesis.     

Molecular pathology of single gene disorders.

Recent studies using recombinant DNA technology have led to an understanding of the basic molecular pathology of single gene disorders. Furthermore, methods are being developed for finding genes for conditions, whose underlying biochemistry is still not understood, or which may contribute to polygenic systems that underlie common diseases. As well as providing new approaches to carrier detection, prenatal diagnosis, and treatment of single gene disorders, these advances promise to provide important information about the pathophysiology of many common polygenic diseases.     

Dealing with uncertainties: ethics of prenatal diagnosis and preimplantation genetic diagnosis to prevent mitochondrial disorders

This paper aims to address the ethical issues regarding prenatal diagnosis and preimplantation genetic diagnosis (PGD) of mitochondrial disorders. Owing to the absence of effective treatment, the prevention of the transmission of mitochondrial disorders is considered to be of key importance. The characteristics of mtDNA, such as heteroplasmy and the genetic bottleneck, make it difficult to estimate recurrence risks correctly and to provide an accurate prognosis for many mtDNA mutations. A limited number of mtDNA mutations allow reliable predictions, though results in the 'grey zone' are problematic. Both prenatal diagnosis and PGD for mtDNA disorders are complicated by the interpretation of the test results. As a consequence, these applications confront both clinical practice and society at large with several ethical questions and issues for further debate, among which the acceptability of suboptimal genetic testing, the value and research use of embryos, the evaluation of late abortion, the ethics of PGD for disorders with an incomplete penetrance and variable expression, the possible transfer of embryos with residual health risks, the acceptability of risks and drawbacks of genetic reproductive technology in general, and the scope and limits of reproductive autonomy and professional responsibility.     

Counseling needs and attitudes toward prenatal diagnosis and abortion in fragile-X families

The genetic counseling need of 32 women of normal intelligence at-risk for having children with the fragile-X syndrome (FXS) were determined by a questionnaire study which included assessment of their attitudes toward prenatal diagnosis and the option of pregnancy termination. Eighteen (56%) of the women had one or more children with the FXS and 14 (44%) had no affected children. Twenty-six (81%) of the subjects stated that they would choose to have prenatal diagnosis and 9 (28%) indicated they would terminate an affected pregnancy. There was no significant difference between women who had affected children and those who did not have affected children, nor between Catholics and non-Catholics regarding acceptance of prenatal diagnosis. Catholic women were less likely to consider pregnancy termination than non-Catholics, but the majority of subjects (56%) were unsure what they would do if a fetus they were carrying was found to be affected. Issues the subjects considered most important for discussion with a genetic counselor included: 1) availability of treatment, 2) risk for having an affected grand child, 3) expectations for future functioning of affected children, and 4) availability of prenatal diagnosis.     

地中海贫血产前筛查及基因诊断研究

目的调查广州市海珠区人群地中海贫血的发生率及及突变基因构成比。方法以来院的产检人群为研究对象,表型分析采用日本System KX-21自动血细胞分析仪测定平均红细胞体积(MCV),美国Helena公司的SPIFE COMBO血红蛋白电泳仪进行血红蛋白分析;基因型确诊运用PCR法或PCR结合反向点杂交(RDB)技术进行地中海贫血常见突变分析。结果在3662例产检人群中,检出α地贫表型阳性897例(24.49%),β地贫表型阳性184例(5.02%)。149例基因诊断阳性病例中,α地贫为107例,β地贫为42例(包括3例是β地贫复合α地贫)。3种常见α地贫缺失型基因的构成比是:--SEA占75.45%;-α3.7占22.73%,-α4.2占1.82%;7种常见β基因突变类型的构成比是:CD41-42占39.53%,IVS2nt654占25.58%,TATAbox-28占13.95%,CD17占6.98%,CD26、CD71/72、TATAbox-29各占4.65%。结论本研究获得了广州市海珠区人群的地贫发生率和基因突变谱的分布特点,为我区开展地贫人群遗传咨询、产前诊断和预防计划提供了有价值的资料。     

Application of droplet digital PCR for non-invasive prenatal diagnosis of single gene disease in two familiesCSCD

Objective To assess the value of droplet digital PCR (ddPCR) for non-invasive prenatal diagnosis of single gene disease in two families. Methods Paternal mutation in cell-free DNA derived from the maternal blood and amniotic fluid DNA was detected by ddPCR. Suspected mutation in the amniotic fluid DNA was verified with Sanger sequencing. Reverse The result of ddPCR and Sanger sequencing indicated that the fetuses have carried pathogenic mutations from the paternal side in both families. Conclusion Droplet digital PCR can accurately detect paternal mutation carried by the fetus, and it is sensitive and reliable for analyzing trace samples. This method may be applied for the diagnosis of single gene diseases caused by paternal mutation using peripheral blood sample derived from the mother. © 2018 West China University of Medical Sciences. All rights reserved.     

β-地中海贫血的基因诊断及产前基因诊断

目的减少β-地中海贫血重症患儿的出生.方法对106例经血液学筛查疑为β-地中海贫血的杂合子携带者行PCR-RDB法进行基因诊断及产前基因诊断.结果共筛出β-地中海贫血阳性患者52例;19例产前基因诊断中,确定正常胎儿9例,重症胎儿2例(纯合子1例,双重杂合子1例),重症β-地中海贫血胎儿诊断后采取引产术终止妊娠.结论PCR-RDB法进行基因诊断及产前基因诊断有效避免了重症患儿的出生,达到了优生的目的.     

In vitro gene amplification for prenatal diagnosis of congenital adrenal hyperplasia.

A simple, rapid, non-radioactive method for detecting homozygous deletions/conversions of the steroid 21-hydroxylase gene is described. In our experience this method will be useful for first trimester prenatal diagnosis of congenital adrenal hyperplasia in 17% of families of a child with the salt losing form. This test includes an internal control to monitor the success of amplification.     

产前超声诊断单脐动脉的临床价值

目的探讨单脐动脉的产前超声诊断及其临床价值。方法对产前超声检查中发现的40例单脐动脉胎儿进一步进行全面筛查,并行脐血染色体检查,对妊娠结局进行随访。结果 40例单脐动脉中,单纯性单脐动脉28例(70%),合并其他畸形12例(30%),其中心血管系统畸形3例,中枢神经系统畸形2例,泌尿系统畸形2例,多发性畸形2例,消化系统畸形、桡骨发育不良及膈疝各1例;接受脐血染色体检查7例,染色体核型异常3例;单纯性单脐动脉预后良好。结论产前超声可以明确诊断单脐动脉。单脐动脉合并其他畸形的发生率高于正常,合并畸形时染色体异常发生率增高。当超声检查发现单脐动脉时,应进一步作系统筛查及染色体检查,并对单脐动脉胎儿生长发育指标进行监测评估,均具有重要的临床意义。