The risk is never zero: experience with rare recessive disease diagnosis in the era of expanded carrier screening

Abstract

Expanded carrier screening (ECS) was launched in 2008 and involves testing for significantly more recessively inherited disorders than are recommended by professional guidelines. Several laboratories have since developed large ECS disease panels. The differences in the number of diseases or genes evaluated, and the methodologies used, are known to vary among these panels, which presents challenges for reproductive risk counseling. Here we document our experience with rare recessive disease diagnoses in donor-conceived offspring to detail additional ECS counseling considerations. At California Cryobank, all reports of medical issues in fetuses or offspring conceived using donor sperm are documented in an Adverse Outcome Report (AOR) and investigated to assess the etiology and risks to other offspring, the donor and his family. If a diagnosis is attributed to a genetic mutation from the donor, distribution of the donor’s specimens is restricted and relevant individuals are informed. AORs received between January 2010 and April 2017 were reviewed to identify all offspring diagnosed with recessively inherited disorders. Cases were further evaluated to determine which diagnoses could have been detected by currently available ECS panels. Six donors were identified as carriers or presumed carriers for recessively inherited disorders based on diagnoses or tests performed on donor-conceived individuals. Carrier screening for each of these conditions is not known to be available on any major ECS panel (Table 1).Tabled 1TABLE 1CaseConditionGene1Friedreich’s AtaxiaFXN2GMPPB-related Muscular DystrophyGMPPB3Adenosine Monophosphate Deaminase 1 DeficiencyAMPD14Adenosine Deaminase 2 DeficiencyCECR15NephronophthisisNPHP16POMT1-related disordersPOMT1 Open table in a new tab Pre-test risk counseling may help to manage patient expectations while planning a pregnancy and assist in the decision-making process for screening prior to, during, and after a pregnancy. In particular, providers should be cautious in informing their patients that ECS involves carrier screening for “all of the most common” or “most severe” recessively inherited disorders. For example, Friedrich’s ataxia has a carrier frequency in the general population of 1/60-1/100[1]. This is a higher carrier frequency than many of the diseases included on ECS panels that have carrier frequencies of less than 1/500. Carrier screening has evolved and improved greatly over the past several decades; however, there is still a background risk for every pregnancy to be affected with a recessively inherited disorder regardless of the carrier screening that was performed on one or both reproductive partners. Addressing the other conditions and background risks that ECS cannot reduce is particularly important for patients using gamete donors since additional screening may not be readily available.