ABSTRACT: The American College of Medical Genetics and Genomics (ACMG) believes that advances in genetic technology should be considered carefully before they become part of routine clinical care. The organization has defined a standard of care for prenatal/preconception population carrier screening for common single-gene autosomal recessive disorders. With advances in genetic sequencing and microarray hybridization analysis, large quantities of disease-specific genetic variants can be determined in a time frame suited to prenatal/preconception screening and diagnosis. Commercial laboratories offer expanded carrier screening panels, but no professional guidance has been forthcoming on which disease genes and mutations to include. The proper selection of appropriate disease-causing targets for general population-based carrier screening should be developed using clear criteria rather than including as many disorders as possible.
Disorders should be of a nature that most at-risk patients and their partners identified would consider having a prenatal diagnosis to facilitate making decisions about reproduction. The inclusion of disorders characterized by variable expressivity or incomplete penetrance and those associated with a mild phenotype should be optional and made transparent when these technologies are used for screening (ethical principle of nonmaleficence).
When adult-onset disorders are included, patients must provide consent to screening for these conditions, especially if they have implications for the health of the individual being screened or other family members (ethical principles of autonomy and nonmaleficence).
For each disorder, the causative genes, mutations, and mutation frequencies should be known in the population being tested to allow meaningful assessment of residual risk in individuals who test negative. Laboratories should specify how residual risk is calculated using pan-ethnic population data or a specific race/ethnic group. This calculation requires knowledge of the carrier frequency within a population and the proportion of disease-causing alleles detected using the specific testing platform. Laboratories offering expanded carrier screening should keep data and regularly report findings that allow calculation of residual risk estimates for all disorders being offered.
There must be validated clinical association between the mutation(s) detected and the severity of the disorder. Materials must include specific citations that support inclusion of the mutations for which screening is being performed.
Quality control and proficiency testing must comply with the ACMG Standards and Guidelines for Clinical Genetics Laboratories and should include the entire process of preanalytic, analytic, and postanalytic phases.
A multifactorial approach will require a more generic consent process than is generally used for single-disease screening because it may not be practical for clinicians to discuss each disease included in a multidisease carrier screening panel. A pamphlet or Web site containing a brief description of each disorder included in a test panel should be available to patients. Genetic counseling before and after testing should be available, especially for those who have positive results. This counseling should include disclosure of the mutation(s) detected, description of the clinical nature of the disorder, facilitation of testing of the reproductive partner, calculation of the revised fetal risk when the partner is not available or declines testing, identification of other at-risk family members, and discussion of options for fetal testing and reproductive decision making.
Divisions of Medical Genetics (W.W.G.) and Molecular Diagnostics, UCLA School of Medicine, Los Angeles, CA (W.W.G.); American College of Medical Genetics and Genomics, Bethesda, MD (B.H.T.); Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL (A.R.G.); Emory Genetics Laboratory, Division of Medical Genetics, Department of Human Genetics, Emory University, Atlanta, GA (L.H.B.); Department of Medical Genetics, Henry Ford Hospital, Detroit, MI (K.G.M); Genetics Division, Department of Pediatrics, Albert Einstein Medical Center, Philadelphia, PA (A.S.); and Department of Pathology and Laboratory Medicine, Akron Children’s Hospital, Akron, (R.V.L.) OH