Epidemiologic Reviews Advance Access published June 27, 2011 Epidemiologic Reviews ª The Author 2011. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. DOI: 10.1093/epirev/mxr008 All rights reserved. For permissions, please e-mail: [email protected]. Genetic Screening Wylie Burke*, Beth Tarini, Nancy A. Press, and James P. Evans * Correspondence to Dr. Wylie Burke, Department of Bioethics and Humanities, A204 Health Sciences Building, Box 357120, University of Washington, Seattle, WA 98195 (e-mail: [email protected]). Accepted for publication March 4, 2011. Current approaches to genetic screening include newborn screening to identify infants who would benefit from early treatment, reproductive genetic screening to assist reproductive decision making, and family history assess- ment to identify individuals who would benefit from additional prevention measures. Although the traditional goal of screening is to identify early disease or risk in order to implement preventive therapy, genetic screening has always Downloaded from included an atypical element—information relevant to reproductive decisions. New technologies offer increasingly comprehensive identification of genetic conditions and susceptibilities. Tests based on these technologies are generating a different approach to screening that seeks to inform individuals about all of their genetic traits and susceptibilities for purposes that incorporate rapid diagnosis, family planning, and expediting of research, as well epirev.oxfordjournals.org as the traditional screening goal of improving prevention. Use of these tests in population screening will increase the challenges already encountered in genetic screening programs, including false-positive and ambiguous test results, overdiagnosis, and incidental findings. Whether this approach is desirable requires further empiric research, but it also requires careful deliberation on the part of all concerned, including genomic researchers, clinicians, public health officials, health care payers, and especially those who will be the recipients of this novel at Curtin University of Technology on June 30, 2011 screening approach. genetic testing; genetics, medical; genomics; heterozygote detection; neonatal screening; prenatal diagnosis INTRODUCTION ease risk and can provide information about genetic suscep- tibilities to many different health risks. Some marketing Screening is conventionally described as the evaluation claims emphasize the health value of single nucleotide poly- of asymptomatic people in a defined population to detect an morphism screening—for example, ‘‘By understanding unsuspected disease or risk in order to improve health out- your genetic predispositions, you can start looking at your come (1). Newborn screening to identify infants who would health in a new way. You can also learn if certain medica- benefit from early treatment is an example and represents tions work with your genetic makeup’’ (13). Tests of this a prominent public health service. Genetic screening is also performed in clinical settings to detect carriers of genetic kind are often referred to as ‘‘genome-scale’’ because they diseases and for prenatal diagnosis, with a different goal: to analyze genetic variation across the full complement of hu- assist reproductive decision making. Both types of screening man genetic material or genome. Numerous genome-scale were started with a focus on specific conditions (Table 1) tests are now available (Table 2) (12, 14, 15), each using (2–9) but have expanded substantially as a result of techno- different methods to measure multiple genetic differences logical advances. simultaneously. New technologies allow multiple genetic risks to be as- The ultimate genome-scale test is whole genome se- certained simultaneously and offer new genetic screening quencing, which ascertains an individual’s complete DNA opportunities—for example, the potential to detect genetic sequence (15). Costs of whole genome sequencing are rap- susceptibilities to common diseases at a level far exceeding idly diminishing. The first human genome sequence was the that of conventional family history assessment (10). One end product of the Human Genome Project, a multinational example of such testing, single nucleotide polymorphism scientific effort that took almost 15 years to complete and microarray testing, is now available directly to consumers cost about $3 billion. However, costs (in the research setting) (11). This type of screening uses an array-based platform are now in the range of $10,000–$50,000 per genome. The (12) to measure multiple gene variants associated with dis- ‘‘thousand-dollar genome’’—perhaps even a hundred-dollar 1 Table 1. Conditions in the Development of Genetic Screening 2 Burke et al. Condition Role in Development of Disease Mechanism Clinical Findings Treatment Options Genetics Current Screening (Reference No.) Genetic Screening Beta-thalassemia Pioneering carrier Reduced synthesis of Severe anemia and Transfusions and chelation Autosomal recessive Carrier and prenatal (2) screening programs hemoglobin beta chain hepatosplenomegaly, therapy; bone marrow inheritance of screening in the Mediterranean leading to failure to thrive transplant mutations in the region (milder forms of disease HBB gene occur with mutations causing milder impairment) Cystic fibrosis (3) First carrier screening Abnormality in cystic Progressive loss of lung Antibiotic and nutritional Autosomal recessive Newborn screening, guideline for fibrosis transmembrane function related to thick lung therapy; lung transplant inheritance of carrier and prenatal nonminority conductance regulator secretions and recurrent mutations in the screening population; first function infections; malnutrition; CFTR gene; >1,000 condition for which male infertility; increased risk mutations identified, randomized of diabetes, pancreatitis, with different levels controlled trial of liver failure (milder forms of of functional newborn screening disease occur with mutations impairment conducted causing milder impairment; some mutations have variable effects) Sickle cell disease Unsuccessful Functional impairment of Hemolytic anemia; vaso- Fluids; pain management; Autosomal recessive Newborn screening, (4) population-based hemoglobin beta chain occlusive events; increased transfusions; prophylactic inheritance of carrier and prenatal carrier screening risk of infections; clinical antibiotic and hydroxyurea hemoglobin S or of screening programs in the course variable therapy; bone marrow hemoglobin S in 1970s; carrier transplant combination with screening now other beta-chain offered in prenatal mutations care; newborn screening initiated in the 1980s Neural tube defects First effort to develop Unknown; results in Variable neurologic impairment Supportive care and Multifactorial; genetic Prenatal screening (5) prenatal maternal failure to close neural symptom management studies identify serum screening; tube during embryologic potential genetic first test offered to development contributors to risk all pregnant women regardless of risk status Phenylketonuria (6) First newborn Total or near-total Severe cognitive impairment Phenylalanine-poor, Autosomal recessive Newborn screening screening programs deficiency of (milder presentations occur tyrosine-enriched diet inheritance of in the 1960s phenylalanine for mutations causing partial mutations in the hydroxylase enzyme deficiency) PAH gene Spinal muscular Most recent carrier Degeneration and loss of Progressive muscle weakness; Supportive care and Autosomal recessive Carrier and prenatal atrophy (7) screening lower motor neurons in different subtypes vary in symptom management inheritance of screening recommendation the spinal cord and the age at onset and range of mutations in the brain clinical manifestations SMN1 or SMN2 gene Tay-Sachs First population-based Total or near total Neural degeneration beginning Supportive care Autosomal recessive Carrier and prenatal disease (8) carrier screening deficiency of at 6 months; death by 4–6 inheritance of screening programs in the hexosaminidase A years (milder presentations mutations in the 1970s occur for mutations causing HEXA gene partial enzyme deficiency) Trisomy 21 (Down First screening use Unknown; chromosomal Cognitive impairment; Educational intervention; Trisomy 21 (small Prenatal screening syndrome) (9) of amniocentesis imbalance results in increased incidence of other surgical and percentage of cases and prenatal impairment congenital heart defects, medical therapy as due to chromosomal chromosome studies hypothyroidism indicated rearrangements resulting in partial trisomy 21) Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; HBB, hemoglobin, beta; HEXA, hexosaminidase A (alpha polypeptide); PAH, phenylalanine hydroxylase; SMN1, survival of motor neuron 1, telomeric; SMN2, survival of motor neuron 2, centromeric. Downloaded from from Downloaded epirev.oxfordjournals.org at Curtin University of Technology on June 30, 2011 30, June on Technology of University Curtin at Table 2. Genome-scale Tests Test (Reference No.) Strengths Limitations Use in Clinical Management Current or Proposed Screening Use Array-based comparative Rapid; adaptable to high throughput/ Does not detect balanced Evaluation of multiple congenital Prenatal genomic hybridization (14) automation; sensitive and specific chromosomal rearrangements anomalies and developmental when validated array used delay Array-based