Fragile X syndrome carrier screening accompanied by genetic consultation has clinical utility in populations beyond those recommended by guidelines

Abstract

BackgroundFragile X syndrome (FXS) is the most common inherited form of intellectual disability. Many providers offer preconception or prenatal FXS carrier screening. However, guidelines recommend screening only for those with a family history or undergoing fertility evaluation. Wider screening has been resisted because of concerns about patient understanding of FXS‐associated inheritance patterns and phenotypes. Additionally, the clinical utility has been questioned.MethodsWe addressed these concerns by analyzing reproductive decision‐making and pregnancy management informed by post‐test genetic consultation among 122 FMR1 premutation carriers identified by expanded carrier screening.ResultsSixty‐three percent of those screened met guidelines screening criteria; the remaining 37% did not. Ninety‐eight percent had undergone post‐test genetic consultation. Of respondents screened preconceptionally, 74% reported planning or pursuing actions to reduce the risk of an affected pregnancy; the extent to which couples planned/pursued these actions was not significantly different between those meeting either screening criterion (76%) versus those meeting neither criterion (55%). Of respondents screened prenatally, 41% pursued prenatal diagnostic testing; the extent to which couples pursued prenatal diagnosis was not significantly different between those who met either screening criterion (37%) versus those who met neither criterion (31%).ConclusionThese results support the expansion of FXS screening criteria in guidelines.

Fragile X Syndrome Secondary to in Vitro Fertilization with a Family Egg Donor, A Case Report and Review of the Literature

“…74 % of couples meeting the criteria for screening versus 55% of couples who didn’t meet the standardized requirements for screening, decided to take action in order to reduce the risk of having a genetically affected child. Furthermore, there weren’t any differences when the diagnosis was made as part of the prenatal studies; therefore, screening for PM carriers of FXS should be open to the general population and not only the group meeting the current criteria for screening ( 37 ).…”

“…The high prevalence of PM carriers for FXS in the general population and therefore the increased risk for FM expansion on to the next generation associated with an increased rate of IVF; pre-conceptional screening for the PM or FM of the FMR1 gene affected in FXS should be considered in every woman undergoing assisted reproductive methods, including gamete donors even without a positive family history of intellectual disabilities ( 3 , 35 , 37 – 39 ).…”

Fragile X premutation and associated health conditions: A review

“…as not meeting the criteria for the screening, 90 as many carriers did not have a family history as specified in the guideline. 91 Accordingly, expansion of the guidelines for FMR1 screening has been proposed.…”

Implementation of fragile X syndrome carrier screening during prenatal diagnosis: A pilot study at a single center

“…However, in light of the high prevalence (~1/150) of PM alleles in Caucasian women and the potential risk conferred by these PM alleles in offspring, many providers advocate universal screening (Archibald et al, 2013 ). Recently, several studies were carried out to explore wider screening for FXS in populations beyond those recommended by the guidelines (Arenas et al, 2017 ; Berkenstadt et al, 2010 ; Johansen Taber et al, 2019 ). Results from these pilot studies were encouraging, whereas practical difficulties such as ethical considerations and cost‐effectiveness of expanded screening existed.…”