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  3. Fragile X syndrome genetic testing

Fragile X syndrome genetic testing

July 20, 2018

Disease summary:

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and one of the leading causes of monogenic forms of autism2. FXS is a repeat disorder caused by the expansion and methylation of CGG trinucleotide repeats in the FMR1 gene to over 200 repeats (Normal allele = 44 repeats). This causes silencing of the gene leading to the absence of the FMRP protein which is needed for normal brain development3. CGG expansions within the FMR1 are also associated with other phenotypes, including a risk of primary ovarian insufficiency in women and the fragile X-associated tremor/ataxia syndrome (FXTAS) when the repeat size is in the range of 55-200 repeats (premutation allele)3. FXS can rarely also be caused by FMR1 point mutations or deletions 4. 

X-linked dominant

1 in 4,000 males

1 in 8,000 females

Major clinical symptoms for FXS 3:

  • Delayed developmental milestones (developmental delay, difficulties siting, walking, speech delay)
  • Intellectual disability (IQ 30-50)  and autism
  • Abnormal facial features (long face, prominent forehead and jaw, large ears)
  • Macroorchidism
  • Strabismus
  • Joint hyperextensibility
  • Flat feet
  • Cardiological defects (mitral valve prolapse, aortic root dilatation)
  • Abnormally soft skin

Major clinical findings for FXTAS 3, 7:

  • Late-onset progressive cerebellar ataxia and intention tremor
  • Short-term memory loss, executive function deficits
  • Cognitive decline
  • Dementia
  • Parkinsonism
  • Peripheral neuropathy
  • Presence of the characteristic clinical features
  • Positive family history of FXS or FXTAS
  • Identification of an expanded CGG repeat allele in the FMR1 gene
  • Identification of other types of pathogenic variants in the FMR1 gene

There is no cure for FXS to date, but symptomatic treatment can relieve symptoms. Management may include the following 3:

  • Special education and early developmental intervention (speech therapy; psychological and physiotherapeutically support and others)
  • Individualized pharmacological treatment for behavioral problems
  • Routine treatment of strabismus, seizures, cardiological problems and others
  • Ongoing clinical trials are testing the potential new therapeutics for Fragile X syndrome 8
  • Sotos syndrome caused by pathogenic variants in NSD1
  • Prader-Willi syndrome (PWS) associated with abnormal imprinting within critical region on chromosome 15
  • Fragile XE syndrome caused by pathogenic variants in the FMR2 gene
  • Rett syndrome caused by pathogenic variants in the MECP2 gene
  • Autism spectrum disorders, Asperger syndrome
  • Attention deficit hyperactivity disorders and disorders with learning difficulties

  • Step 1: Repeat Expansion/Fragment Length Analysis is recommended as the first step as:

    • higher fraction of cases observed to carry disease-causing repeat expansion in CentoMD® over SNVs/CNVs
    • higher number of disease-causing expansions have been documented in public literature

  • Step 2: FMR1 gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter.
  • Step 2: FMR1 deletion/duplication analysis/pathogenic variant scanning using MLPA/qPCR

  • Males with intellectual disability and/or autism
  • Individuals with most common symptoms of FXS (regardless of family history)
  • Individuals with the clinical a positive family history of FXS or FXTAS

Confirmation of a clinical diagnosis through genetic testing of Fragile X syndrome can allow for genetic counseling and may direct medical management.