Genomics in general practice

Disease specific topics

Fragile X syndrome and associated conditions

Fragile X syndrome and associated conditions

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 evidence of primary ovarian insufficiency (associated with elevated follicle-stimulating hormone [FSH]).
  • Adults with tremor or cerebellar ataxia of unknown origin to diagnose fragile X-associated tremor/ataxia syndrome (FAXTAS). Mean onset of FAXTAS is ~60 years of age but can present before age 50. 

What do I need to know?

FXS

FXS is the most common 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.

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.

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

Females who are premutation carriers (55 – 199 CGG repeats) can have a child affected with FXS. This is because the repeat length can get longer when passed from mother to child: this lengthening only occurs in women. Therefore, it is very unlikely males who are premutation carrier of FXS would have a child with FXS.

Associated conditions

Females who are premutation carriers Recessive genetic conditions such as cystic fibrosis (CF) occur when a person inherits a particular genetic variant from each parent. A carrier is an individual who only has one copy of the gene variant Gene variants and generally does not have symptoms, but can pass the variant to their children. Some conditions are due to a pathogenic variant in a gene on the X chromosome (X-linked inheritance). Typically, these conditions affect more males (who have the sex chromosomes XY) than females (who have the sex chromosomes XX). A woman who is a carrier of an X-linked condition has the variation on one of her X chromosomes, which she can pass on to her children. However, if the biological male has a pathogenic variant in an X chromosome gene, he will not pass it to his sons, but will pass it to all of his daughters. are at increased risk of FXPOI. Both males and females with a premutation are at increased risk of fragile X-associated tremor/ataxia syndrome (FXTAS) later in life with the risk being higher for males than females.

Genetic testing

Chromosome microarray (CMA) is now considered a first-line genetic test for the investigation of DD or congenital abnormalities. However, CMA does not detect gene variants Gene variants are small DNA sequence changes (ie additions, duplications, deletions, substitutions). These variants can have a range of effects: some may cause disease (pathogenic variant), while others do not cause disease but may modify an individual’s risk of disease (i.e may increase risk or provide a protective effect). The vast majority of gene variants are benign and do not result in disease but rather contribute to the differences between people. causing FXS, so an additional DNA test for FXS must be also ordered.

DNA testing for FXS is available with an MBS rebate when the patient:

  • exhibits ID, ataxia, neurodegeneration, or primary ovarian insufficiency consistent with an FMR1 mutation
  • has a relative with an FMR1 mutation

GPs should offer information on carrier screening for FXS to all couples planning a pregnancy (or who are already pregnant), regardless of family history or ethnicity. Refer to Reproductive carrier screening for more information.

When should I refer?

For symptomatic patients:

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

Asymptomatic patients with a test positive result (eg received through pre-conception or prenatal Carrier screening Carrier screening is a test to determine whether an individual carries a genetic variant that does not generally affect that individual’s health, but increases his or her chance of having children with the condition in question. The outcome of such testing can influence future reproductive decisions. Carrier screening is performed on individuals who are not necessarily known to be at increased risk for a particular genetic condition. Screening tests can be conducted on individuals from specific groups such as those from a common ethnic background (eg: screening for Tay-Sachs disease carrier status in the Ashkenazi Jewish community) or entire populations. or cascade testing) should be referred to genetics services.

Further reading

  • Birch RC, Cohen J, Trollor Fragile X-associated disorders: Don’t miss them. Aust Fam Physician 2017;46(7):487–91. [Accessed 6 September 2022].
  • Finucane B, Abrams L, Cronister A, et 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.
  • RANZCOG Genetic carrier screening. 2019. 
  • Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine (2021) 23:1793–1806
  • Miller DT, Adam MP, Aradhya S, et 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.
  • Department of Medicare Benefits Schedule (MBS) Online. Canberra: DoH, 2022. [Accessed 11 February 2022].

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