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Abstract

Fragile X Syndrome (FXS) is an X-linked disorder characterized by a CGG trinucleotide repeat located within the 5’ untranslated region of the Fragile X Mental Retardation 1 gene (FMR1). The FMR1 gene is further categorized into classifications of protein function such as normal, intermediate, premutation or full mutation depending on the number of CGG repeats present²³. A normal FMR1 gene produces a sufficient amount of the Fragile X Mental Retardation Protein (FMRP) and exhibits anywhere between 5 and 44 repeats. An allele in intermediate range displays 45-54 repeats with FMRP production as the normal range. As the number of repeats increases, methylation of the gene increases as well; along with the decreased production of FMRP²³. A premutation allele occurs when 55-200 CGG repeats are present and exhibits lower levels of FMRP. When alleles fall into this range, they are subject to expansion when transmitted into subsequent generations. Additionally, female carriers are at risk for inheriting Fragile X-associated Primary Ovarian Insufficiency (FXPOI), which causes the ovaries to not work correctly. A full mutation displays complete methylation of the FMR1 gene, no FMRP production, and greater than 200 repeats. An individual diagnosed with a full mutation for FXS exhibits developmental and behavioral issues that include, but are not limited to, intellectual impairment, failure to meet milestones, and lack of impulse control²⁰.

Due to the severity of a full mutation of FXS, FXPOI and the risk of expansion, female patients will seek reproductive assistance from infertility specialists. Assisted reproductive techniques have been developed; such as preimplantation genetic diagnosis (PGD)¹². Due to these advances in clinical and laboratory practice, improvements have been made in in-vitro fertilization (IVF) outcomes. The success has increased greatly with the application of PGD¹². A current method of testing embryos for FXS involves the use of quantitative Polymerase Chain Reaction (qPCR)-based SNP genotyping linkage analysis. The inheritance pattern of the affected allele is tracked throughout this process; however, the number of repeats present is not observed. The determination of CGG repeats is a crucial addition to current methods of testing to avoid the risk of expansion and to assist patients in obtaining a healthy pregnancy¹².

Advisory Committee

• Dr. Carlos A. Molina (Chair)
• Dr. ChunguangDu
• Dr. Emre Seli