New directions in cytogenetic and molecular testing of the neonate

The development of new diagnostic, and hence therapeutic possibilities, has brought the realization that genetic disease is now an integral part of medical practice. Advances in cytogenetic and molecular testing have drastically improved the ability to diagnose with certainty many previously unrecognized conditions. However, this advance in technology does not come without new questions. New tests are not always the most cost effective ones, some have significant diagnostic limitations, and others raise valid ethical issues surrounding the testing of minors. A working understanding of new advances in genetic diagnosis as well as their inherent limitations is crucial for the contemporary practitioner.     

Performance of lecithin-sphingomyelin ratio as a reflex test for documenting fetal lung maturity in late preterm and term fetuses

Objective: To determine if infants delivered after immature or indeterminate TDx-FLM II testing and a mature reflex test are at increased risk for neonatal respiratory complications. Methods: The primary analysis compared neonatal respiratory morbidity (RDS or TTN) in 34–39-week fetuses delivered after either (i) mature TDx-FLM II testing, or (ii) indeterminate or immature TDx-FLM II and a positive reflex test (PG or L/S ratio). Results: Fifty patients delivered after mature TDx-FLM II, and 30 after immature or indeterminate TDx-FLM II with an L/S ≥2.0. Respiratory morbidity was significantly higher in the group delivered after mature reflex testing compared with mature TDx-FLM II (23% vs. 2%, p?<?0.01). When PG was present, there were no cases of RDS or TTN. Conclusions: Utilizing L/S ratios as a reflex test to confirm lung maturity was associated with a high risk for respiratory morbidity, particularly when PG was not present.     

Drug screening and criminal prosecution of pregnant women

According to the U.S. Supreme Court, the Fourth Amendment rights of 10 women were violated by a hospital that provided them prenatal care. The incidence of prenatal drug testing for criminal prosecution with or without a woman's knowledge is increasing. Concurrently, funding and availability of drug treatment programs for pregnant women are declining. Nurses and physicians who act as advocates for the state rather than the patient damage the patient-provider relationship and breach their ethical responsibility to the patient.     

Condition-specific antepartum fetal testing

OBJECTIVE: The purpose of this study was to determine the best available antepartum fetal testing methods according to the underlying pathophysiologic condition. STUDY DESIGN: We reviewed the current literature and our clinical experience with respect to condition-specific antepartum fetal testing. RESULTS: The efficacy of most antepartum tests that we use today is not supported by randomized controlled clinical trials, but from observational nonrandomized studies and expert opinion (evidence levels II or III). CONCLUSION: Based on the available evidence, the accuracy of a test depends on the underlying pathophysiologic condition. To improve accuracy, we must use condition-specific fetal testing.     

Mucolipidosis type IV a rare genetic disorder: new addition to the Ashkenazi Jewish panel

Mucolipidosis type IV (MLIV) is a rare genetic disorder that primarily affects persons of Ashkenazi Jewish descent. Current information available about testing options and the Ashkenazi Jewish Screening panel, including the addition of screening for MLIV, is presented. The importance of genetic screening and counseling is emphasized.     

Newborn screening and genetic testing

New screening techniques and diagnostic tests for genetic diseases available for newborn screening can provide information about many diseases long before they are clinically detected. However, this information creates complex questions and ethical dilemmas regarding which newborns should be tested, when testing should occur, availability and costs of tests, and how families should be counseled. There is no national policy regarding newborn screening, which leads to great variation among states' newborn screening programs. This article reviews newborn genetic testing and provides a blueprint for clinicians to improve practice by incorporating into their care knowledge of new developments in newborn testing and screening.     

Parent's attitudes towards full-scale prenatal testing for genetic disorders

Objectives. Innovations in the field of prenatal diagnostic testing have led to the development of molecular tests that allow the rapid detection of specific genetic defects, such as Down syndrome. In addition, full-scale tests have been developed allowing the detection of many genetic disorders in a single test. Here we examined the attitudes of pregnant women in low risk pregnancies towards full-scale genetic testing and explored relationships between demographic characteristics and the level of interest.

Methods. A prospective study was performed on 115 consecutive pregnant women. They completed the same structured questionnaire at two different time points, before counselling (T1) and after 4 weeks (T2), to assess a possible change of attitude.

Results. At T1, 33% of the respondents were in favour of full-scale testing of their unborn child, whereas at T2, this percentage had dropped to 18%. Except for educational level, no significant relationships were noted between the demographic variables and the wish to opt for full-scale testing. A low educational level was significantly related to the interest in full-scale testing.

Conclusions. Low risk pregnant women expressed little interest in full-scale genetic testing. Educational level appeared to affect their views.     

Implications of multigene testing for hereditary breast cancer in primary care

Approximately 1 in 8 women will develop breast cancer during their lifetime and the risk factors include age, family history, and reproductive factors. In women with a family history of breast cancer, there is a proportion in which a gene mutation can be the cause of the predisposition for breast cancer. A careful assessment of family and clinical history should be performed in these women in order to determine if a genetic counseling referral is indicated. In cases of hereditary breast cancer, genetic testing with a multigene panel can identify specific genetic mutations in over 100 genes. The most common genes mutated in hereditary breast cancer are the high-penetrance BRCA1 and BRCA2 genes. In addition, other mutations in high-penetrance genes in familial cancer syndromes and mutations in DNA repair genes can cause hereditary breast cancer. Mutations in low-penetrance genes and variants of uncertain significance may play a role in breast cancer development, but the magnitude and scope of risk in these cases remain unclear, thus the clinical utility of testing for these mutations is uncertain. In women with high-penetrance genetic mutations or lifetime risk of breast cancer > 20%, risk-reducing interventions, such as intensive screening, surgery, and chemoprevention, can decrease the incidence and mortality of breast cancer.     

Ethical and legal aspects of noninvasive prenatal genetic diagnosis

The new technology that will allow genetic testing of a fetus within the first trimester of pregnancy by isolating cell-free fetal DNA (cffDNA) in the mother’s blood raises a range of ethical and legal issues. Considered noninvasive, this test is safe and reliable, and may avoid alternative genetic testing by amniocentesis or chorionic villus sampling, which risks causing spontaneous abortion. Ethical and legal issues of cffDNA testing will become more acute if testing expands to fetal whole-genome sequencing. Critical issues include the state of the science or diagnostic art; the appropriateness of offering the test; the implications of denying the test when it is available and appropriate; disclosure and counseling following test results; and management of patients’ choices on acquiring test results. A challenge will be providing patients with appropriate counseling based on up-to-date genetic knowledge, and accommodating informed patients’ legal choices.     

Human immunodeficiency virus testing in patients with invasive cervical carcinoma: a prospective trial of the gynecologic oncology group

To determine the frequency of positive human immunodeficiency virus (HIV) serostatus among North American women 50 years of age or younger with invasive cervical cancer and to define their tolerance to treatment. Consenting patients with newly diagnosed invasive cervical cancer, age 50 or younger were tested by enzyme-linked immunosorbent assay. The study design anticipated that approximately 3% of patients would be HIV positive. After the accrual of 913 eligible and evaluable patients, interim analysis revealed that only 9/913 ( approximately 1%) patients were HIV seropositive, indicating that it would not be feasible to achieve the study objective. The study was closed to further accrual. Between 1994 and 1997, the frequency of positive HIV serostatus among North American women with newly diagnosed cervical cancer was quite low. As a consequence, no evaluation of response to treatment or treatment tolerance can be made.     

What Regulations for Preimplantation Genetic Diagnosis?

PURPOSE: To discuss the qualifications of personnel involved in either (a) embryo biopsy/slide fixation, (b) performance of preimplantation genetic diagnosis-specific assays, or (c) interpretation of findings and results from such studies. METHODS: Illustrate similarities and differences between the qualifications and licensing requirements for personnel involved in high complexity testing in other laboratory specialities, such as microbiology or endocrinology. RESULTS: Parallels can in fact be drawn between specific personnel certification and licensing requirements for reporting test results following preimplantation genetic testing and those for other clinical specimens submitted for testing. CONCLUSIONS: Assisted reproductive technology programs generally do not have personnel certified in cytotechnology or clinical genetics. Programs that perform the actual interpretation of specimens submitted for evaluation by fluorescent in situ hybridization will have to have supervisory personnel certified to perform such interpretations to ensure the level of quality control and assurance now afforded in centers for assisted reproductive technology.     

Antenatal testing: diabetes mellitus

Diabetes complicating pregnancy is a problem for which fetal surveillance testing is considered to be the standard of care. In response to the unacceptable frequency of stillbirth in such pregnancies, fetal testing historically was first introduced to manage women whose pregnancies were complicated by diabetes. Essentially all forms of antepartum testing have been used to assess fetal well-being during the third trimester of pregnant diabetics. The contraction stress test became established as the "gold standard," yet other testing protocols have been used successfully. It is clear that control of diabetes throughout gestation, not just in the later stages, is more important for optimal outcome than is a specific form of fetal testing. Biweekly testing has become the standard and with well-controlled diabetics, allowing the gestation to continue until the onset of spontaneous labor, even when the gestation exceeds 40 weeks, is appropriate management with normal testing.     

The significance of meconium in midtrimester genetic amniocentesis

Since the advent in recent years of midtrimester amniocentesis for genetic testing, there has been an increasing number of reports of occasional instances of meconium-stained amniotic fluid of uncertain prognostic significance. Previous reports have suggested a fetal mortality of 30%. With larger series now available for study, more accurate information on the incidence of this occurrence and its significance is presented. The present series consists of 4709 consecutive amniocenteses performed from 1978 to 1983, at two genetic testing centers in Portland, Oregon. Meconium-stained amniotic fluid was found in 79 cases, for an incidence of 1.67%. Contrary to previously published reports, the fetal mortality was 5.06%. Thus the finding of meconium-stained amniotic fluid during midtrimester genetic amniocentesis may not carry the ominous prognosis that originally might have been predicted.