Genomics in general practice


Fragile X syndrome and associated conditions
☰ Table of contents


Practice point


General practitioners (GPs) can order a test for Fragile X syndrome (FXS) for the following people:

Individuals with intellectual disability (ID), developmental delay (DD) or autism spectrum disorder (ASD).

Individuals seen for reproductive counselling who have a family history of FXS (or related conditions, such as Fragile X-associated primary ovarian insufficiency [FXPOI]) or undiagnosed ID.

Women with reproductive or fertility issues (associated with elevated follicle-stimulating hormone [FSH]).

Older individuals (>50 years of age) with late-onset tremor or cerebellar ataxia of unknown origin.

 


What do I need to know?


FXS

FXS is the most common known inherited cause of ID, and the second most common cause of ID overall (after Down syndrome). FXS affects approximately one in 3600 males and one in 6000 females.1

FXS presents clinically with a wide range of symptoms, including global DD; difficulties with learning, speech and language; problems with coordination and sensory overload; and notably a range of emotional and behavioural difficulties.2,3

FXS follows an X-linked recessive inheritance pattern and is caused by an increase in length of the FMR1 gene on the X chromosome. The length of the FMR1 gene is divided into four categories (Figure 1). The longer the gene, the more likely the individual will have symptoms of FXS.2,3

Figure 1. Length of gene associated with FXS

Females who are premutation carriers of FXS can have a child affected with FXS. This is because the gene length can get longer when passed from mother to child: this lengthening only occurs in women. Therefore, it is unlikely males who are premutation carrier of FXS would have an affected child.4


Associated conditions

Females who are premutation carriers are at increased risk of FXPOI. Males (females to a lesser extent) are at increased risk of Fragile X-associated tremor/ataxia syndrome (FXTAS) later in life.2,3,4

 

Genetic testing


Chromosome microarray (CMA) is now considered a first-line genetic test for the investigation of DD or congenital abnormalities. CMA does not detect gene variants causing FXS, so an additional deoxyribonucleic acid (DNA) test for FXS must be ordered alongside.5

While GPs are able to order CMAs, many choose not to, given the complex interpretation of the results. However, ordering CMA and FXS tests in parallel with referral to a paediatrician can reduce waiting times for patients.

A Medicare Benefits Schedule (MBS) rebate is available for CMA in situations where the patient has DD, ID, ASD or at least two congenital abnormalities. DNA testing for FXS is available with an MBS rebate when the patient:6

  • exhibits ID, ataxia, neurodegeneration, or premature ovarian failure consistent with an FMR1 mutation
  • has a relative with an FMR1 mutation.

 

When should I refer?


For symptomatic patients:

  • A child with a test positive result should be referred to a paediatrician for further assessment.
  • An adult with ataxic symptoms and a test positive result (ie premutation carrier) should be referred to a neurologist.
  • A woman with FXPOI should be referred to an obstetrician and gynaecologist.2,3

Asymptomatic patients with a test positive result (eg received through pre-conception or prenatal carrier screening or cascade testing) should be referred to genetics services.

 

Resources for patients


Information

National Library of Medicine (US),Fragile X syndrome

Support

Fragile X Association of Australia

 


Genomics in general practice




 

 

  1. Birch RC, Cohen J, Trollor JN. Fragile X-associated disorders: Don’t miss them. Aust Fam Physician 2017;46(7):487–91.[Accessed 19 December 2017].
  2. Finucane B, Abrams L, Cronister A, et al. Genetic counseling and testing for FMR1 gene mutations: Practice guidelines of the National Society of Genetic Counselors. J Genet Couns 2012;21(6):752–60.
  3. Metcalfe S, Jacques A, Archibald A, et al. A model for offering carrier screening for fragile X syndrome to nonpregnant women: Results from a pilot study. Genet Med 2008;10(7):525–35.
  4. Abrams L, Cronister A, Brown WT, et al. Newborn, carrier, and early childhood screening recommendations for fragile X. Pediatrics 2012;130(6):1126–35.
  5. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010;86(5):749–64.
  6. Department of Health. Medicare Benefits Schedule (MBS) Online. Canberra: DoH, 2017. [Accessed 19 December 2017].

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