Newborn screening: new developments, new dilemmas

Scientific and technological advances are lending pressure to expand the scope of newborn screening. Whereas this has great potential for improving child health, it also challenges our current perception of such programmes. Standard newborn screening programmes are clearly justified by the fact that early detection and treatment of affected individuals avoids significant morbidity and mortality. However, proposals to expand the scope and complexity of such testing are not all supported by a similar level of evidence for unequivocal benefit. We argue that screening for genetic susceptibility to complex disorders is inherently different from standard screening and, while of potential value, must be considered separately from conventional testing.     

Proceduralisation, choice and parental reflections on decisions to accept newborn bloodspot screening

Newborn screening is the programme through which newborn babies are screened for a variety of conditions shortly after birth. Programmes such as this are individually oriented but resemble traditional public health programmes because they are targeted at large groups of the population and they are offered as preventive interventions to a population considered healthy. As such, an ethical tension exists between the goals of promoting the high uptake of supposedly 'effective' population-oriented programmes and the goal of promoting genuinely informed decision-making. There is, however, a lack of understanding with regard to how parents experience the tension between promoting uptake and facilitating informed choice. This paper addresses this issue, and data are presented to show how aspects of the timing, presentation of information and procedural routinisation of newborn screening serves to impact on the decisions made by parents.     

The role of low birthweight in the aetiology of type 2 diabetes

The aetiology of type 2 diabetes is still poorly understood. Although it is clear that obesity is a risk factor for the disease, obesity leads to diabetes only in susceptible individuals. Both genetic and environmental factors determine this susceptibility. This review describes the emerging evidence that low birthweight caused by malnutrition or a genetic predisposition increases the risk of type 2 diabetes.     

Ethical issues in preconception genetic carrier screening

Population-based preconception genetic carrier screening programmes (PCS) with expanded panels are currently being developed in the Netherlands. This form of genetic screening for recessive traits differs from other forms of genetic testing and screening in that it is offered to persons not known to have an increased risk of being carriers of genetic traits for severe recessive diseases and in that they include tests for a large number of traits, potentially several hundred. This raises several ethical issues around justice, consequences, and autonomy. It will be argued that most of these ethical problems call for cautious reflection when setting up PCS and similar programmes within preconception care. It is moreover argued that it is ethically problematic to have an official aim and failing to mention possibly legitimate public aims that actually drive the development of PCS.     

美国的医学遗传检测

Genetic tests for about1000health conditions have been developed,of which more than600are currently a-vailable for clinical testing[1].Many genetic tests identify DNAvariants;others measure biochemical markers or an-alyze chromosomes.Most are used for dia…     

一种筛查中国人遗传性耳聋和氨基糖苷耳毒性易感人群的分子遗传学方法

Objective: To develop a molecular screening test for genetic defects on hearing loss related genes has significant impacts on early identification of hereditary hearing loss and genetic susceptibility to aminoglycoside ototoxicity. Early identification of pre-lingual hearing loss is very important for patient‘s language development, academic achievement, and social skill. Two common mutations, the 235delC in GJB2 gene and the mutation A1555G in mitochondrial DNA, are included in the newly developed screening panel for Chinese population. Methods: A molecular genetic assay, based on fluorescent labeled multiplex PCR and automatic DNA fragment analyzing techniques, was developed to detect both mutations simultaneously. Results: This assay was able to detect both mutations from patient‘s samples, and pooled DNA tests, as well as suitable to detect mutation from the DNA extracted from dried blood spot and buccal swab. Conclusion: This assay could be a useful tool for newborn screening and carrier screening for the hereditary hearing loss for the Chinese population。     

新生儿听力与聋病易感基因联合筛查的临床实践研究

目的 探讨新生儿听力和聋病易感基因联合筛查的临床实践的可行性.方法选择从2012年9月-2013年7月在该市出生的6 057例新生儿进行听力和聋病易感基因的联合筛查,同时进行动态筛查及基因检测,新生儿听力动态筛查分初筛和复筛,初筛以快速脑干诱发电位（AABR）为主要筛查方式,如果不通过,30~42 d复筛,复筛不通过转诊该院耳鼻喉科诊断,采用如畸变产物耳声发射（DPOAE）,脑干听觉诱发电位（ABR）,声导抗、多频稳态反应（ASSR）、CT等检查进行综合评估;同时对新生儿进行基因筛查,采取6 057例新生儿脐带（或足跟血）以检测常见易感基因（线粒体12S rRNA、SLC26A4（PDS）、GJB2）的突变情况.结果 动态听力筛查未通过新生儿375例,所占比例6.19%;耳鼻喉科诊断有120例中度听力损失、131例重度听力损失、80例极重度听力损失、44例听力正常.对6 057例新生儿行基因检测显示193例新生儿基因异常,其中1例为1494C〉T纯合突变、2例1555A〉G杂合突变、16例1555A〉G纯合突变、7例2168A〉G杂合突变、46例IVS7-2A〉G杂合突变、1例IVS7-2A〉G纯合突变、101例235delC杂合突变、4例235delC纯合突变、11例299_300delAT杂合突变、4例176_191del16杂合突变,阳性率为3.19%.结论新生儿听力和聋病的易感基因联合筛查作用显著,可以发现新生儿中存在和聋病相关的遗传基因,从而弥补其他筛查不能发现聋病新生儿的不足.     

Diabetes in Australian aboriginal and Torres Strait Islander peoples

Type 2 diabetes arises from a complex and multifactorial set of factors, including genetic susceptibility, behaviour (including diet and exercise), early nutrition, obesity and psychosocial stress, leading to insulin resistance and pancreatic failure. These factors in turn are influenced by social and physical environmental factors. Each of these may be important determinants of the high prevalence and incidence of type 2 diabetes in Australian Aboriginal and Torres Strait Islander people. Public health interventions for primary and secondary prevention need to recognize this complexity. Although a reduction in the prevalence of obesity or diabetes in the short-medium term is rarely if ever achieved, there are documented examples of community-based programs which have been effective in reducing the risk of developing type 2 diabetes and its cardiovascular complications. Such interventions need to be community-directed and appropriate to local circumstances in order to be effective.     

The natural history and the national pre-marital screening program in Saudi Arabia

The genetic disorders are chronic in nature and, therefore, require continuous support and health care. Consequently, the genetic diseases cause formidable economic and psychosocial burdens on the family with negative reflection on the community at large. The genetic diseases are a heterogeneous group that result in varieties of chronic health ailment as a result of defects in the genetic material. The congenital malformations and some genetic defects may result from exposure to radiation, pharmaceutical drugs, the exposure of the mother during pregnancy to certain infectious diseases, such as rubella, toxoplasma or viruses. It may also result as a side effect of chronic diseases, including diabetes, hypertension or varieties of environmental factors, or both. The other group of genetic diseases are transmitted from parents to the offspring through a specific pattern of inheritance exemplified by recessive genetic disorders. This group includes the sickle cell gene, the thalassemias, the hemophilias, inborn errors of metabolism and red cell enzymopathies. The main etiological factors of genetic diseases and congenital malformations are 1) Genetic defects which are transmitted to offspring through carriers of affected parents. 2) Mutations in the genetic materials due to spontaneous mutations, exposure of the mother during pregnancy to infectious diseases, such as rubella and toxoplasma, receiving certain teratogenic drugs during pregnancy, exposure of the mother to ionizing radiation during pregnancy such as x-ray and chronic diseases of the mother, such as diabetes mellitus. 3) Others such as difficult labor or injury to the baby, during or after labor. This paper reviews the natural history of common blood genetic disorders and the means of prevention and control, focusing on pre-marital screening as a means of prevention.     

中国人早发糖尿病家系的临床特征及MODY1基因突变的筛查

目的探讨家族性早发2型糖尿病的临床特点及MODY1基因与家族性早发2型糖尿病遗传易感性的关系.方法收集2型糖尿病家系,其中早发家系190个,晚发家系103个.采集临床数据及完善相应的检查,同时选取其中100个早发糖尿病家系的先证者进行基因突变筛查,用PCR扩增MODY1基因的全部编码区,并直接测序分析.SPSS进行统计分析.结果 (1)早发2型糖尿病先证者的甘油三酯、空腹胰岛素、HomaIR值、父母亲患糖尿病人数高于晚发组.(2)在早发糖尿病患者中,肥胖组的诊断年龄、高密度脂蛋白低于非肥胖组,而甘油三酯、胰岛素水平、HomaB、HomaIR高于非肥胖组.(3)MODY1基因筛查结果:Exon1c M49V (82%);Exon4 T130 I (4%);Exon10 S462S (1%);IVS1c 44A→T(6%);IVS2 -5C→T(33%).结论 (1)跟晚发相比,早发家族性2型糖尿病有更多的父母亲患病,遗传和肥胖在家族性早发2型糖尿病的发病中起了重要作用.(2)在早发糖尿病家系中,MODY1是少见的,HNF-4α基因不是中国人早发糖尿病的主要致病基因.     

高通量红细胞血型基因分型的多重连接依赖的探针扩增技术在一例抗Di~a新生儿溶血病诊断中的应用

目的运用高通量红细胞血型基因的多重连接依赖的探针扩增技术(multiplex ligation-dependent probe amplification,MLPA)辅助诊断一例罕见的由抗Di~a导致的严重核黄疸新生儿溶血病。方法运用传统的血型血清学方法对导致新生儿溶血病相关红细胞血型抗体进行鉴定,运用MLPA对患儿及其父母的超过40种红细胞血型抗原进行基因分型,对鉴定的抗体进行效价分析。结果血型血清学检测表明患儿体内含有针对某种低频抗原的抗体,MLPA基因分析结果提示母婴红细胞MNS血型系统及Diego血型系统抗原不匹配,可能存在抗N或抗Di~a,经进一步的血型血清学检测,证实母亲及患儿血清中存在抗Di~a,并且其母亲血清抗Di~a效价为1:32。结论抗Di~a可引起包括核黄疸在内的严重新生儿溶血病;高通量红细胞血型基因分型的MLPA技术能够协助并有效解决临床疑难样本稀有血型鉴定;针对国人的Di~a阳性的试剂红细胞应该常规应用于日常的抗体筛查工作中。     

XPC、XPG基因单核苷酸多态性与肿瘤遗传易感性关系的研究进展

肿瘤的发生是多基因参与、多因素作用的复杂过程,是基因-基因、基因-环境的交互作用导致的结果。XPC、XPG基因是DNA损伤修复系统中核苷酸切除修复途径的核心基因,这2个基因存在单核苷酸多态性,影响个体患肿瘤的遗传易感性,并与相关环境暴露因素存在交互作用,影响肿瘤的患病风险。XPC、XPG基因单核苷酸多态性的研究结果对评价遗传与环境因素对肿瘤的危险性、阐明肿瘤发生的分子遗传学机制、明确肿瘤高危个体以及肿瘤早期诊断和治疗等有重要意义。     

The clinical geneticist and the "new genetics"

The "new genetics" will provide new genetic tests that can be used for diagnosis, prognosis, treatment selection, carrier and predictive testing in affected families, and potentially for susceptibility testing for later-onset multifactorial disease and population screening. Doctors will increasingly need to consider the family implications of a genetic diagnosis--to identify family members at risk of the disorder or of having affected children and to consider how these individuals might be advised of their situation. Clinical geneticists can be a valuable resource for doctors who need advice about whether genetic testing is available, which tests to pursue, how to access testing services, and how to interpret and act on test results. Clinical geneticists also provide genetic counselling, a process which gives people understandable information about the genetic disorder in the family, and makes the information useful for decision-making given the person's unique circumstances and beliefs. The Internet will increasingly be a key source of information about genetic disorders for patients, their families and healthcare professionals.     

Hereditary spherocytosis in a newborn with carrier state parents--a family study

A four-hour-old male newborn was diagnosed as hereditary spherocytosis by routine blood examination. There was no family history of anemia, jaundice or splenectomy. Osmotic fragility and autohemolysis tests were positive both in patient and parents. However there were no abnormal findings in physical and routine blood examinations of parents and a sibling. Hereditary spherocytosis is rather a difficult diagnostic problem during the neonatal period when there is no family history. The clinical manifestation and unusual genetic carrier pattern in the parents are discussed.     

History of medical screening: from concepts to action

The objective of medical screening is to identify disease in its preclinical, and therefore hopefully still curable, phase. This may have been an old quest in medicine but it became historically possible when at least four conditions were met: the availability of simple, valid and acceptable forms of tests, the discovery of effective treatments, the establishment of a theory of screening, and the wide access to health care. Five selected examples that illustrate the history of medical screening are reviewed: screening for psychiatric disorders in the United States army as it is one of the oldest screening programmes; screening for syphilis as it used one of the earliest screening tests; screening for diabetes as one of the first modern forms of mass screening; screening for cervical cancer using the Pap test as one of the greatest successes of screening; and screening for breast cancer by mammography as this offers a good opportunity to discuss the development of modern evaluation of screening programmes. The evaluation of the impact of screening on human health slowly progressed, from obvious changes in the vital statistics such as the decline in incidence of syphilis, to less obvious changes such as the decline in mortality of cancer of the uterus, to finally more subtle changes, such as the impact of mammographic screening on breast cancer mortality. Methods of evaluation had therefore to adapt, evolving from simple surveys to case-control studies and randomised trials. The history of screening is short, but very rich and mostly still to be written.     

新生儿遗传病基因筛查技术及相关疾病

新生儿遗传病筛查目前以代谢物生化指标检测为主,检测结果假阳性率较高,且有一定的假阴性,筛查的病种较少。近几年逐步开展的新生儿遗传病筛查基因检测技术包括定量聚合酶链反应技术和高通量测序。高通量测序又分为基因包测序、全外显子组测序和全基因组测序。但目前用于新生儿遗传病筛查的基因技术主要为定量聚合酶链反应技术和基因包测序。新生儿基因筛查病种由单病种筛查如耳聋、脊髓性肌萎缩及重症联合免疫缺陷病等向多病种筛查发展。新生儿基因筛查结果解读除遵循美国医学遗传学与基因组学学会联合分子病理协会在2015年提出的“序列变异解读标准和指南”外,还需要结合生化指标检测及其他检测结果综合分析。新生儿遗传病基因筛查的开展需要遵循伦理原则,包括将新生儿基因筛查作为公共卫生项目的伦理、新生儿及其家庭成员知情选择权和隐私权伦理等。新生儿遗传病基因筛查的开展将使更多的遗传病患者能够早期诊断,改善其预后,在新生儿遗传病筛查领域具有里程碑意义。     

Lack of awareness of risk factors for primary toxoplasmosis in pregnancy

Background

The overall seroprevalence of toxoplasma antibodies in women of childbearing age in Ireland is 25% [1]. Hence, 75% of women remain susceptible to primary toxoplasma infection during pregnancy, which if transmitted to the foetus can cause ocular, neurological and other sequelae. Toxoplasma exposure during pregnancy can be avoided if there is an awareness of the potential sources of infection, mainly contaminated food, water, soil and cat faeces.

Aims

To determine risk factor exposure in a cohort of women with congenitally infected infants and to assess maternal risk awareness prior to diagnosis of infection.

Methods

Data, prospectively gathered during 2 years of pilot newborn screening for congenital toxoplasmosis in Ireland, was retrospectively analysed. Known risk factors for acquisition of infection were identified. Women were questioned regarding risk awareness and implementation of avoidance measures, if any, during pregnancy.

Results

Fifteen congenitally infected infants were identified by newborn screening. Seventy-three percent of their mothers (11/15) reported lack of knowledge concerning risk factors for toxoplasma infection or its potential threat to the foetus. Ingestion of raw or undercooked meat during pregnancy was the predominant source of toxoplasma cyst exposure identified. Contact with cats was reported in just one case.

Conclusions

Most women were uneducated about the risks posed by Toxoplasma gondii exposure during pregnancy. There is a clear need for better educational programmes regarding primary prevention of congenital toxoplasmosis if neonatal infection is to be avoided.     

Peroxisome proliferator activated receptor gamma Pro12Ala: old topic of conversation and new question

Comments concerning Meta analysis for relationship between peroxisome proliferator activated receptor gamma Pro12Ala polymorphism and type 2 diabetes susceptibility in different cohorts in this mini review were given. The comments pointed out existent problems and presented suggestions for genetic analysis of diseases in Chinese populations.     

Ethical issues arising from human genetics.

Advances in understanding genetic disorders have been rapid in the last few years and with them the need and desire for genetic counselling have grown. Almost simultaneously, particularly in the USA, several large screening programmes have been initiated to screen large numbers of people who may be carriers of such deleterious genes as those of Tay-Sachs disease and sickle cell anaemia. The authors of this paper, clinical medical students at University College Hospital, London, spent some time studying the ethical issues raised. The first part of their study, which is not published here, relates to the biochemistry of certain genetic disorders, so leading up to the aspect of the subject which must concern readers of this journal, genetic counselling. At present genetic counselling is generally the province of the medical practitioner working with clinical biochemists, and in this paper their function is described and how programmes of screening for carriers are designed. Whether the subjects of the screening tests are found to be 'innocent' or 'guilty' psychological problems confront them, and of these the genetic counsellor must be aware. In fact the range of ethical problems raised by such counselling is wide and can only be sketched in this article.     

Genetic screening in Western Australia.

The wider application of genetic screening is described in four Western Australian populations. Counselling with prenatal diagnosis of Down's syndrome was offered to 57 women over the age of 35 years and less than 16 weeks' gestation who attended an antenatal outpatients department. Forty-four women consented to amniocentesis and two affected fetuses were found. Both public and private patients can be screened to detect fetuses with Down's syndrome. In a population of 200 pregnant girls whose infants were intended for adoption, a specially designed family history form aided identification of genetic disorders in 32 families. Counselling was offered to the biological parents, to the adoptive parents, and, prospectively, to the child in later years. The effectiveness of the family history as a screening device is illustrated in this adoption sample. Counselling of parents of 20 decreased malformed infants initiated the genetic counselling clinic in Western Australia and led to subsequent referral of 92 similar cases by the family doctors. It was found that parents who gave birth to malformed infants welcome information and risk figures. Diagnostic screening in a population of 6000 intellectually handicapped individuals yielded 1372 cases (23%) with Mendelian, multifactorial, or chromosomal modes of inheritance. This screening enabled patients with inherited causes for their intellectual handicap to be identified and placed on a register for health planning.