title: Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders.
abstract: Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS)) relies on a combination of polymerase chain reaction (PCR) and Southern blot (SB) for the fragile X mental retardation 1 (FMR1) CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test. The newer and more robust triplet-primed PCR or TP-PCR assays allow the mapping of AGG interruptions and enable the predictive analysis of the risks of unstable CGG expansion during mother-to-child transmission. In this review, we have summarized the correlation between several molecular elements, including CGG-repeat size, methylation, mosaicism and skewed X-chromosome inactivation, and the extent of clinical involvement in patients withFMR1-related disorders, and reviewed key developments in PCR-based methodologies for the molecular diagnosis of FXS, FXTAS and FXPOI, and large-scale (CGG)nexpansion screening in newborns, women of reproductive age and high-risk populations.
authors.affiliation: Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore. indhushree_rb@u.nus.edu.
authors.forename: Indhu-Shree
authors.initials: IS
authors.lastname: Rajan-Babu
authors.affiliation: Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore. paecs@nus.edu.sg.|Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore 119228, Singapore. paecs@nus.edu.sg.|Department of Laboratory Medicine, National University Hospital, Singapore 119074, Singapore. paecs@nus.edu.sg.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Chong
keywords: AGG interruption; CGG repeat; FMR1; FXPOI; FXTAS; fragile X syndrome; melting curve analysis; methylation; screening; triplet-primed PCR