The American College of Obstetricians and Gynecologists has identified additional resources on topics related to this document that may be helpful for ob-gyns, other health care providers, and patients. The American College of Obstetricians and Gynecologists has previously recommended offering carrier screening for four conditions in the Ashkenazi population: Canavan disease is a severe degenerative neurologic disease. Diagnostic tests generally have lower false-positive and false-negative rates but can be more expensive and/or more invasive. DNA-based molecular analysis (eg, Southern blot analysis and polymerase chain reaction) is the preferred method of diagnosis of fragile X syndrome and of determining FMR1 triplet repeat number (eg, premutations). Variant of uncertain significance ( i.e., VUS) : A category of variants in a gene where the variant cannot be placed into either of the above four categories. Mol Genet Genomic Med 2013;1:260–8. If red blood cell indices indicate a low mean corpuscular hemoglobin or mean corpuscular volume, hemoglobin electrophoresis also should be performed. Repeats very rarely expand during spermatogenesis in the male, such that only an affected male can transmit the full mutation to his female offspring. Mutation : When referring to changes in the sequence of a gene, this term has generally been replaced by “variant.” Variant has less stigmatization and is less definitive, allowing for classification according to its relationship with a condition of interest (e.g., benign, pathogenic). With these changes, new terminology has appeared, whereas old terms and their definitions have evolved. If you belong to an ethnic group or race that has a high rate of carriers for a specific genetic disorder, carrier screening for these disorders may be recommended. Type A is the most common form in the Jewish population. If a couple knew they were at risk, the child could be tested during pregnancy or right at birth to know if the child was affected. Affected individuals can experience bone marrow failure; increased risk of cancer, including leukemia and solid tumors; and structural defects such as short stature, skin pigment changes, nervous system abnormalities (including central nervous system malformations), eye and ear malformations and hearing loss, skeletal abnormalities in particular affecting the thumb or forearms, gastrointestinal abnormalities (including effects on the oral cavity), and others. The possible genetic combinations are summarized in Table 3. The fundamental challenge of diagnostic and prenatal screening is identifying which variants in a gene can cause genetic conditions. Pan-ethnic screening : This is an approach to carrier screening where all ethnic groups are screened the same way. -globin gene; this alteration causes a substitution of valine for glutamic acid in the number six position of the β-globin polypeptide. The following are various carrier screening scenarios with associated management recommendations: A woman is a carrier of a cystic fibrosis mutation and her partner is unavailable for testing or paternity is unknown. Therefore, it is difficult to accurately predict the couple’s risk of having a child with the disorder. There have been considerable coordinated efforts such as ClinGen to distinguish which variants are benign versus pathogenic for disease. Therefore, the counseling of patients who are tested for carrier status must account for the residual risk present when carrier screening assay results are negative, particularly in patients from families affected by spinal muscular atrophy. Type 1F and Type III appear to be the most common in the Jewish population. When only one partner is of Ashkenazi Jewish descent, that individual should be offered screening first. In patients with a family history of spinal muscular atrophy, molecular testing reports of the affected individual and carrier testing of the related parent should be reviewed, if possible, before testing to determine the residual risk for the patient with a negative screen. If nothing else, treatment could start in the event that testing did come back with a positive result. The syndrome occurs in approximately 1 in 3,600 males and 1 in 4,000–6,000 females from a variety of ethnic backgrounds. If the reports are not available, SMN1 deletion testing should be recommended for the low-risk partner. Beta-thalassemia major is characterized by severe anemia with resultant extramedullary erythropoiesis, delayed sexual development, and poor growth. This and other abnormal hemoglobins, when inherited with hemoglobin S, may cause clinically significant vasoocclusive phenomena and hemolytic anemia similar to hemoglobin SS. If the reports are not available, SMN1 deletion testing should be recommended for the low-risk partner. There is almost always a false-negative rate (e.g., residual risk). Given that cystic fibrosis screening has been a routine part of reproductive care for women since 2001, it is prudent to determine if the patient has been previously screened before ordering repeat cystic fibrosis screening. Carrier screening and counseling ideally should be performed before pregnancy because this enables couples to learn about their reproductive risk and consider the most complete range of reproductive options, including whether or not to become pregnant and whether to use advanced reproductive technologies such as preimplantation genetic diagnosis or use of donor gametes.