Carrier screening for Beta-thalassaemia: a review of international practice

β-thalassaemia is one of the most common single-gene inherited conditions in the world, and thalassaemia carrier screening is the most widely performed genetic screening test, occurring in many different countries. β-thalassaemia carrier screening programmes provide a unique opportunity to compare the delivery of carrier screening programmes carried out in different cultural, religious and social contexts. This review compares the key characteristics of β-thalassaemia carrier screening programmes implemented in countries across the world so that the differences and similarities between the programmes can be assessed. The manner in which thalassaemia carrier screening programmes are structured among different populations varies greatly in several aspects, including whether the programmes are mandatory or voluntary, the education and counselling provided and whether screening is offered pre-pregnancy or antenatally. National and international guidelines make recommendations on the most appropriate ways in which genetic carrier screening programmes should be conducted; however, these recommendations are not followed in many programmes. We discuss the implications for the ethical and acceptable implementation of population carrier screening and identify a paucity of research into the outcomes of thalassaemia screening programmes, despite the fact that thalassaemia screening is so commonly conducted.     

Different options for prenatal testing for Huntington''s disease using DNA probes.

The discovery of DNA markers closely linked to the gene for Huntington's disease (HD) has allowed development of predictive and prenatal testing programmes for HD. This report describes four different approaches to prenatal testing for HD which have arisen during a pilot predictive and prenatal testing program in British Columbia, Canada. In the first approach (exclusion testing), the at risk parent cannot or prefers not to learn of his/her HD status. Two other approaches involve definitive testing of a fetus when a parent is determined to be at increased risk to have inherited the HD gene or is affected with Huntington's disease. The fourth approach is a stepwise combination of the above two methods which we refer to as 'exclusion-definitive' testing. These different approaches introduce a variety of challenging counselling and ethical issues. The role of each approach to prenatal testing in the management of Huntington's disease awaits the results of this and other predictive and prenatal testing programmes.     

Inherited Metabolic Disorders in Adults: A view from Saudi Arabia

The incidence of inherited metabolic disorders (IMD) in Saudi Arabia is one of the highest in the world. Early diagnosis and advances in the treatment of these diseases have led to improved survival of these patients resulting in a rapidly growing number of adults with IMD. This is the first report from a single tertiary care center, on the experience of managing a large cohort of adult patients with a wide range of IMD. We describe the common IMD seen in adult patients in Saudi Arabia, highlighting the variations from the Caucasian populations, and unique challenges in providing care to these adults. We mention the pitfalls causing the delay in the diagnosis particularly in cases of late-onset IMD in adults. We also discuss some unusual complications seen in adult patients during the course of their disease. We describe the role of genetic prevention services in Saudi Arabia and the importance of research in this field.     

Associated malformations in the family of a patient with Meckel syndrome: heterozygous expression?

Meckel syndrome is an inherited autosomal recessive disease. A family is described in which four persons had minor malformations related to the syndrome, suggesting the possibility of manifesting heterozygotes. It is uncertain whether these malformations represent partial expression of the disease or are coincidental. However, partial expression has been described in heterozygotes for other autosomal recessive diseases. Until the gene responsible for this lethal syndrome is cloned and sequenced, such relatives of the proband may be offered genetic counselling and prenatal diagnosis.     

Screening for hereditary diseases. What other screening?

Faced to the success of the neonatal screening for phenylketonuria and congenital hypothyroidism, it was tempting to introduce screening of other metabolic diseases. "Ideal" diseases to be screened are treatable, are not easily recognized by clinical means during the neonatal period, need immediate therapy to prevent irreversible disabilities, have a reasonable frequency and can be detected by and easy test. There is some controversy concerning the list of diseases recommended for mass screening, among them four can be discussed: congenital adrenal hyperplasia, due to 21-hydroxylase deficiency, fulfils most of the criteria, but some changes in the general screening strategy should be made to provide a result as soon as possible, and at least before the 10th day of life; cystic fibrosis, immunoreactive trypsin is a good marker of the disease but its assay needs technical adaptation for mass screening; more information are also required about the efficacy of an early management of the disease; Duchenne muscular dystrophy has a good marker for neonatal screening (creatine kinase), but no treatment exists and the possibility of genetic counselling can only be provided; hypercholesterolaemia is a frequent disease; however, the good marker and the adequate treatment remain to be defined. Pilot programmes, on the behalf of the French Association for Neonatal Screening, are evaluation these problems. However, at the present time, a consensus has been reached that only phenylketonuria and hypothyroidism fulfils criteria for an efficient mass screening programme.     

The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis

BACKGROUND: Cell-free fetal nucleic acids (cffNA) can be detected in thematernal circulation during pregnancy, potentially offeringan excellent method for early non-invasive prenatal diagnosis(NIPD) of the genetic status of a fetus. Using molecular techniques,fetal DNA and RNA can be detected from 5 weeks gestation andare rapidly cleared from the circulation following birth. METHODS: We searched PubMed systematically using keywords free fetalDNA and NIPD. Reference lists from relevant papers were alsosearched to ensure comprehensive coverage of the area. RESULTS: Cell-free fetal DNA comprises only 3–6% of the total circulatingcell-free DNA, therefore diagnoses are primarily limited tothose caused by paternally inherited sequences as well as conditionsthat can be inferred by the unique gene expression patternsin the fetus and placenta. Broadly, the potential applicationsof this technology fall into two categories: first, high geneticrisk families with inheritable monogenic diseases, includingsex determination in cases at risk of X-linked diseases anddetection of specific paternally inherited single gene disorders;and second, routine antenatal care offered to all pregnant women,including prenatal screening/diagnosis for aneuploidy, particularlyDown syndrome (DS), and diagnosis of Rhesus factor status inRhD negative women. Already sex determination and Rhesus factordiagnosis are nearing translation into clinical practice forhigh-risk individuals. CONCLUSIONS: The analysis of cffNA may allow NIPD for a variety of geneticconditions and may in future form part of national antenatalscreening programmes for DS and other common genetic disorders.     

Patient and parental attitudes toward genetic screening and its implications at an adult cystic fibrosis centre

General population screening for cystic fibrosis carrier status in the United Kingdom would detect 72% of at-risk couples. Proper counselling would allow these couples to make informed reproductive choices, including the possibility of prenatal diagnosis and the termination of an affected pregnancy. However, children with cystic fibrosis born in this decade, given optimum treatment, now have an average life expectancy of 40 years, and there is no unanimity of opinion on how, where, when, or even if, screening should be offered. The purpose of this questionnaire-based study was to examine the attitudes of an adult clinic population who have grown up with cystic fibrosis, and of their parents, towards genetic screening programmes and the controversies and ethical dilemmas surrounding such programmes in cystic fibrosis. Both patients and parents supported prenatal screening (88% and 90%) and the option of terminating an affected pregnancy (68% and 84%). Only 22% of patients and 10% of parents felt that screening should be limited to families with a history of cystic fibrosis, and 19% and 6%, respectively, that prenatal diagnosis should be restricted to those with a previous child with cystic fibrosis. Despite the negative aspects of any screening programme and the acknowledged ethical problems peculiar to cystic fibrosis, the conclusion of our patients and parents who have lived intimately with the illness is that there should be the option of utilising information available from genetic screening for cystic fibrosis to guide reproductive choices. Pilot programmes to define the optimum management of such screening should continue.     

Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens

Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10,000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n = 72,453) and prenatal diagnosis (n = 121) for this condition. Our analysis of large-scale population carrier screening data (n = 68,471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11,000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.     

Inherited skeletal muscle disorders

The field of inherited skeletal muscle disease research has advanced rapidly since the identification of mutations in the dystrophin gene as the cause of Duchenne muscular dystrophy in 1987. From that point, an ever-increasing number of the genes associated with inherited muscle diseases have been identified. These discoveries have led to much more accurate diagnosis of the individual diseases and have allowed prenatal diagnosis where this was not previously possible. The major challenges for the future are to understand the pathophysiology of the diseases, now that the genes are being identified, and then to develop successful therapies.     

Clinical applications of tandem mass spectrometry: ten years of diagnosis and screening for inherited metabolic diseases

This paper reviews the clinical applications of tandem mass spectrometry (MS-MS) in diagnosis and screening for inherited metabolic diseases in the last 10 years. The broad-spectrum of diseases covered, specificity, ease of sample preparation, and high throughput provided by the MS-MS technology has led to the development of multi-disorder newborn screening programs in many countries for amino acid disorders, organic acidemias, and fatty acid oxidation defects. Issues related to sample acquisition, sample preparation, quantification of metabolites, and validation are discussed. Our current experience with the technique in screening is presented. The application of MS-MS in selective screening has revolutionized the field and made a major impact on the detection of certain disease classes such as the fatty acid oxidation defects. New specific and rapid MS-MS and LC-MS-MS methods for highly polar small molecules are supplementing or replacing some of the classical GC-MS methods for a multitude of metabolites and disorders. New exciting applications are appearing in fields of prenatal, postnatal, and even postmortem diagnosis. Examples for pitfalls in the technique are also presented.     

A national perspective on prenatal testing for mitochondrial disease

Mitochondrial diseases affect >1 in 7500 live births and may be due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Genetic counselling for families with mitochondrial diseases, especially those due to mtDNA mutations, provides unique and difficult challenges particularly in relation to disease transmission and prevention. We have experienced an increasing demand for prenatal diagnostic testing from families affected by mitochondrial disease since we first offered this service in 2007. We review the diagnostic records of the 62 prenatal samples (17 mtDNA and 45 nDNA) analysed since 2007, the reasons for testing, mutation investigated and the clinical outcome. Our findings indicate that prenatal testing for mitochondrial disease is reliable and informative for the nuclear and selected mtDNA mutations we have tested. Where available, the results of mtDNA heteroplasmy analyses from other family members are helpful in interpreting the prenatal mtDNA test result. This is particularly important when the mutation is rare or the mtDNA heteroplasmy is observed at intermediate levels. At least 11 cases of mitochondrial disease were prevented following prenatal testing, 3 of which were mtDNA disease. On the basis of our results, we believe that prenatal testing for mitochondrial disease is an important option for couples where appropriate genetic analyses and pre/post-test counselling can be provided.     

The global problem of genetic disease

Inherited haemoglobin disorders will undoubtedly cause an increasing health burden in many developing countries. Although much is known about their molecular pathology and the mechanisms for their phenotypic diversity, many important questions remain, not least the role of the environment in modifying the clinical course. Methods for screening these conditions are now well established and inexpensive and it is vital that they are applied to define the magnitude of the problem that will be posed by these conditions in the future. Similarly, they form the basis for widespread screening and counselling programmes directed at developing prenatal diagnosis expertise where this is not available. Answers to some relatively simple questions about the role of the environment could also make a major difference to the management of the haemoglobin disorders. There is a major case for the development of regional networks to apply such technology as has been developed for the control and prevention of the important haemoglobin disorders, particularly in Asian countries.     

治疗性引产31例缺陷儿临床分析

目的探讨产前诊断对出生缺陷疾病诊断的临床意义,提高产前诊断率,降低出生缺陷发生率。方法通过孕期系统B超、产前筛查、染色体病产前诊断方法进行产前检查,分析2009年9月～2010年12月本院产前诊断的出生缺陷胎儿病例资料。结果 2549例孕妇通过系统B超、产前筛查、染色体病产前诊断等技术共诊断并引产缺陷胎儿31例,出生缺陷检出率为1.22%。结论通过产前超声检查、产前筛查技术、羊水染色体检查,及早地发现缺陷儿并及时终止妊娠,是减少出生缺陷发生的有效措施。     

αβ复合型地中海贫血的分子检测及血液学分析

目的通过对αβ复合型地中海贫血的分子基因型的检测及血液学的表型分析,了解其基因分布状况及发生率。方法采用单管多重缺口-PCR法和反向膜杂交法,对396例地中海贫血筛查阳性的样本进行α地中海贫血和β地中海贫血的基因诊断。结果在396例样本中,检出单纯性α地中海贫血109例(27.5%),单纯性β地中海贫血115例(29.0%),αβ复合型地中海贫血26例(6.57%)。αβ复合型地中海贫血占β地中海贫血的18.44%。αβ复合型地中海贫血共有7种基因型,涉及5种β地中海贫血突变类型(CD41-42、IVS-2-654、TA;TA;box-28、CD71-72、43)和2种α地中海贫血缺失类型(α地中海贫血-1基因和α地中海贫血-2基因)。红细胞参数(MCV、MCH及Hb)在αβ复合型地中海贫血与单纯性β-地中海贫血之间的差异不具有统计学意义(P>0.05)。结论αβ复合型地中海贫血双重杂合子的发生率较高,且缺乏特异性的血液学指标。对β地中海贫血筛查阳性的病人应同时进行α和β地中海贫血基因诊断,以减少αβ复合型地中海贫血漏检的可能,以便下一步正确地指导遗传咨询和产前诊断。     

Counselling for prenatal diagnosis of sickle cell disease and beta thalassaemia major: a four year experience.

A non-directive programme of prenatal counselling was used during a four year period. Forty-three couples at risk for having a baby with a haemoglobinopathy were identified. Prenatal diagnosis was offered in 19 pregnancies to 14 couples at risk of having a baby with sickle cell anaemia and in two pregnancies in two couples at risk of a baby with beta thalassaemia major, who presented before the 18th week of pregnancy. Six couples at risk for sickle cell anaemia accepted prenatal diagnosis in 10 pregnancies, as did both couples at risk for thalassaemia. Couples who were eligible for prenatal diagnosis but refused it tended not to have been informed about sickle cell disease before counselling, one partner was more frequently absent at the time of the initial counselling session, or they either had no children with sickle cell disease or the children were not severely affected. Other factors influencing their decision included a poor obstetric history and rejection of abortion, mainly on moral grounds. The approximately 50% uptake of prenatal diagnosis in this initial study highlights the complex issues involved. Our experience indicates that with systematic screening and counselling in the antenatal clinic, and with increased awareness of the haemoglobinopathies, couples at risk will be in a better position to make informed decisions.     

Human genome project: a federator program of genomic medicine

The Human Genome Project improves our understanding of the molecular genetics basis of the inherited and complex diseases such as diabetes, schizophrenia, and cancer. Information from the human genome sequence is essential for several antenatal and neonatal screening programmes. The new genomic tools emerging from this project have revolutionized biology and medicine and have transformed our understanding of health and the provision of healthcare. Its implications pervade all areas of medicine, from disease prediction and prevention to the diagnosis and treatment of all forms of disease. Increasingly, it will be possible to drive predisposition testing into clinical practice, to develop new treatments or to adapt available treatments more specifically to an individual's genetic make-up. This genomic information should transform the traditional medications that are effective for every members of the population to personalized medicine and personalized therapy. The pharmacogenomics could give rise to a new generation of highly effective drugs that treat causes, not just symptoms.     

母血清、超声及联合筛查对出生缺陷产前诊断的比较性研究

目的探讨母血清生化指标、产前超声及联合筛查对出生缺陷产前诊断的价值。方法回顾性比较研究自2001年1月至2009年12月前行产前检查或遗传咨询的12 221例孕妇,依据其接受产前检查的项目分为血清组、超声组和联合组。筛查后对有介入性产前诊断指征者在超声引导下进行羊水或脐血采集并行染色体分析,确诊是否有染色体异常。结果接受检查的12 221例孕妇中血清组共计6091例,超声组共计5110例,联合组共计1021例。全部孕妇共检出出生缺陷儿937例。其中血清组孕妇中共筛查出高风险孕妇450例,检出染色体异常12例。超声组共检查出胎儿发育异常739例,共检出染色体异常52例。联合组发现胎儿发育异常的孕妇一共有162例,检出染色体异常30例。应用统计学χ2检验进行两两比较,在对染色体异常的检测上,超声的检测率比血清筛查的检测率明显增高（P〈0.05）,而超声与母血清联合筛查的检测率比单纯超声筛查的检测率高（P〈0.05）。结论血清生化指标筛查占用卫生资源较少,方法易掌握,可作为某些染色体病普及性筛查的首选方法;超声筛查为无创性,可重复性高,不受孕周限制,并可检出更多的结构异常;而酌情联合应用血清生化指标筛查和超声筛查,可明显提高染色体异常的检出率,降低筛查假阳性率。     

串联质谱技术在新生儿遗传代谢病筛查中的应用

遗传代谢病是一组种类繁多,临床症状复杂的疾病,常累及神经系统等多器官,一旦发病危害严重。通过新生儿筛查技术早发现早治疗是预防遗传代谢病危害的有效途径。现对串联质谱技术在新生儿遗传代谢病筛查应用中的技术原理、实验流程、面临的挑战和问题作综述。     

Mendelian inheritance of polygenic diseases: a hypothetical basis for increasing incidence

The incidence of common polygenic diseases, such as type 1 diabetes, bronchial asthma, and gluten-sensitive enteropathy, is increasing. Although this is usually attributed to environmental factors, it is possible that this rising incidence also has a genetic basis. The hypothesis is put forth that, in the past, these diseases, with their increased morbidity and mortality, were selected against. In contrast to monogenic diseases, the incidence of polygenic diseases can be reduced by selection against susceptibility alleles of any of the genetic loci necessary for disease to occur. In different isolated populations, different disease susceptibility loci may have been selected against. Parents who derive from different isolated populations in which there are inversely different susceptibility allele frequencies because of selection or genetic drift, would be expected to have offspring with an increased risk for that polygenic disease. It is shown mathematically that the incidence of a hypothetical polygenic disease increases under these circumstances. The increased risk in these offspring results from a kind of genetic complementation in which they have inherited a more complete set of susceptibility alleles at all susceptibility loci than is carried by either of their parents. Hallmarks of this hypothesized phenomenon would be increased heterozygosity for specific population markers (whether susceptibility alleles or not) among the disease-affected offspring and a paucity of such heterozygotes among their parents. The parents and patients would also be expected to give more evidence of ethnic or subethnic disparity than that observed in controls.     

Cervical cancer screening in India: strategies revisited

With the change in the life styles and demographic profiles of developing countries, noncommunicable diseases are emerging to be important health problems that demand appropriate control program before they assume epidemic proportion. One of these is the problem of cancer. In India, cervical cancer is a significant problem in terms of incidence, mortality and morbidity. Cervical cancer is a disease that can be prevented through both primary prevention and early detection using screening techniques. Several screening modalities are now available for early detection of cervical cancer and its precursor lesions. They all differ with regard to their test characteristics, feasibility and economic considerations. This communication reviews different aspects of these screening modalities and provides different options considering mass application.