Spotlight on Fragile X syndrome

• By Variantyx, Inc
• Posted in Clinical Education

Fragile X syndrome (FXS) is one of the most common heritable forms of intellectual disability, occurring in approximately 1 in 4,000 males and 1 in 8,000 females. Patients are most often diagnosed at roughly 3 to 4 years of age after a lengthy period of evaluation and testing.

Signs and symptoms of fragile X syndrome can, but do not always, include:

• Delayed development of speech and language
• Mild to moderate intellectual disability
• Anxious, fidgitive or hyperactive behavior, including attention deficit disorder
• Social and communication issues common to autism and autism spectrum disorders
• Characteristic dysmorphic features such as prominent ears, a long and narrow face, and large testes after puberty
• Seizures

The disorder is caused by mutation of the X-linked FMR1 gene, typically affecting males more severely than females. In nearly all cases, the causative mutation is an expansion of the unstable CGG repeat sequence present in the 5’ UTR of the gene. FMR alleles are roughly categorized into four classes: normal (up to 40 repeats), intermediate (41 to 60 repeats), premutation (61 to 200 repeats) and full mutation (>200 repeats). Full mutation alleles are typically hypermethylated, resulting in silencing of the gene which leads to no mRNA production and the associated phenotypes. The relevance of intermediate alleles is not completely clear, but (due to FMR1’s X-linkage) females carrying one copy of a premutation allele have a 50% chance of passing the allele on to their offspring, with a high likelihood that the number of repeats within the allele will be further expanded during transmission. Males carrying a premutation allele have a 100% chance of passing the allele on to their daughters, but the likelihood of further expansion during transmission is very low.

Individuals with premutation alleles do not have fragile X syndrome, but may show symptoms of two fragile X-associated disorders: fragile X-associated primary ovarian insufficiency and fragile X-associated tremor/ataxia syndrome. These disorders frequently go unrecognized within a family making it important to evaluate a child’s maternal family history for presence of female relatives with early menopause or fertility problems or for presence of older male relatives with ataxia or Parkinson’s like tremors.

Fragile X syndrome can not be detected by standard chromosome tests or microarrays and has traditionally required a separate, specific FMR1 test for fragile X. Through a combination of whole genome sequencing (WGS) and customized algorithms, the Genomic Unity™ test (in additional to analyzing small sequence changes, structural variants and mitochondrial variants) specifically analyzes the FMR1 region for the number of CGG repeats. When the normal threshold of 40 repeats is exceeded, the variant is flagged for more targeted follow up and validation.

Although there is not a cure for fragile X syndrome, diagnosis can be critical for providing access to educational techniques that work with an individual’s strengths and weaknesses, raising awareness of potential associated medical conditions to be screened for as well as identifying relevant behavioral treatment methods. Diagnosis also enables family members to seek connections with other families who are navigating the challenges of raising a child with fragile X syndrome and to receive genetic counseling for family planning.