XSense®, Fragile X with Reflex

Laboratory assay overview

Fragile X syndrome (FXS OMIM # 300624) is the most common inherited mental retardation syndrome, affecting approximately 1:4000 males and approximately 1:8000 females. The disease is caused by the expansion of a trinucleotide CGG repeat in the 5'-untranslated (UTR) region of the FMR1 gene. Methylation of the expanded CGG tract leads to silencing of expression of the FMR1 gene. The American College of Medical Genetics defines a normal repeat length as between 5 and 44. Intermediate alleles of between 45-54 repeats almost never expand to full mutations in a single meiosis. Premutation alleles are defined as 55-200 CGG. Premutation alleles of less than 90 repeats have a variable risk for expansion to full mutations whereas larger premutation alleles almost always expand when inherited through a female. Full mutation alleles are defined as >200 repeats. FXS in an X-linked dominant disease. The test is used to detect the presence of expanded alleles in the FMR1 gene and to distinguish normal homozygous females from full mutation carriers.

Laboratory assay overview

This test panel can be used to detect abnormalities in the FMR1 gene and chromosome abnormalities. Results may be useful for determining the cause of intellectual disability (ID)/developmental delay (DD) and for informing reproductive counseling for individuals with a family history of ID/DD. An increased number of CGG repeats in the FMR1 gene may cause fragile X syndrome (FXS), fragile X-associated primary ovarian insufficiency (FXPOI), or fragile X-associated tremor ataxia syndrome (FXTAS) [1]. If an expanded allele (>85 CGG repeats) is detected, methylation analysis will be performed reflexively to help determine premutation or full mutation status. Chromosome abnormalities may be linked to several conditions, including infertility, miscarriage, birth defects, ID, and DD. FXS is the most common inherited form of ID and typically affects males more severely than females. Full mutations (>200 repeats) cause FXS, while premutations (55-200 repeats) confer an increased risk of FXPOI, for females, and FXTAS, primarily for older males. The reflex methylation analysis helps determinate hypermethylation status, an indicator of FMR1 gene silencing. It can also detect a mosaic condition in which the CGG repeat number is in the full mutation range, but subpopulations of cells have no hypermethylation. Testing for FXS and related disorders may be considered for individuals with ID, DD, autism spectrum disorder, POI, or intention tremor and ataxia [1]. This test can also be used to identify FXS carriers and determine an individual's risk of having a child with FXS. Chromosome analysis detects trisomies, such as trisomy 21 (Down syndrome), trisomy 13, and trisomy 18, and sex chromosome abnormalities such as Turner (45,X) and Klinefelter (47,XXY) syndromes. Chromosome analysis also detects microscopically visible chromosomal rearrangements, including Robertsonian translocations, reciprocal translocations, inversions, marker chromosomes, and chromosomal mosaicism at or above 14%. Disorders that cannot be detected with this panel include most microdeletion syndromes, such as DiGeorge, Prader-Willi, Angelman, Williams, and Smith-Magenis; single-gene disorders, such as FXS caused by deletions and point mutations of FMR1; and chromosomal mosaicism below 14%. Although FXS and chromosome abnormalities are common causes of ID/DD, many other genetic causes can lead to ID/DD. In the absence of clinical suspicion for a specific genetic disorder, a chromosomal microarray analysis (test code 16478) is recommended by the International Standards for Cytogenomic Arrays Consortium as the first-tier cytogenetic diagnostic test for patients with unexplained ID/DD, autism spectrum disorders, or multiple congenital anomalies [2]. The components of this panel are also available separately. The results of this test should be interpreted in the context of pertinent clinical and family history and physical examination findings. For more information on this test, or other genetic tests that might be appropriate, please contact Quest Genomics Client Services at 1.866.GENE.INFO (1.866.436.3463). References 1. Spector E, et al. Genet Med. 2021;23(5):799-812. 2. Miller DT, et al. Am J Hum Genet. 2010;86(5):749-764.