Fragile X syndrome

Fragile X syndrome is an X-linked genetic condition that results in intellectual disability and characteristic dysmorphic features. It usually presents in early childhood and is the most common inherited cause of intellectual disability in boys. It affects about 1 in 4,000 people of both sexes, although females are usually affected less severely.

Clinical features of fragile X syndrome include:

• moderate to severe intellectual disability in boys;
• mild to moderate intellectual disability in heterozygous females (about 50% of cases – the others will be intellectually normal);
• social communication and behavioural issues (such as autism spectrum disorder, seen in 50%–70% of cases);
• characteristic appearance in boys (may only be present in older children):
  • long, thin face with frontal bossing and prominent chin;
  • macrocephaly (or a normal-sized head, but not typically microcephaly); and
  • large, protruding ears;
• mild connective tissue dysplasia (such as hypermobile joints or mitral valve prolapse);
• macroorchidism after puberty in affected males; and
• family history of developmental delay or intellectual disability, premature ovarian insufficiency and/or adult-onset neurological features, including ataxia and tremor, consistent with X-linked inheritance.

Fragile X syndrome is a triplet-repeat expansion disorder.  It is caused by pathogenic expansion of a CGG triplet repeat region within the FMR1 gene, located on the X chromosome. Pathogenic expansion of the repeat region to over 200 repeats, often termed ‘full mutation’, leads to hypermethylation, repression of FMR1 expression and deficiency of the FMR1 protein.

The list below provides an overview of the clinical significance of various numbers of CCG repeats that might present clinically.

• Under 41 repeats (most commonly 29 or 30), termed ‘normal allele’: The patient is unlikely to have fragile X syndrome (although there are rare cases with deletions or point variants in FMR1):
• 41 to 54 repeats, termed ‘intermediate allele’: This is slightly less stable than the normal repeat, and may expand over several generations.
• 55 to 200 repeats, termed ‘premutation allele’ . The higher the number of repeats (especially once they surpass 90), the more unstable the repeats are and the greater the chance of expanding to a ‘full mutation’. Certain phenotypes are additionally associated with premutation status.
• Over 200 repeats, termed ‘full mutation’. Boys with this many repeats will usually be affected with fragile X syndrome. Girls may be variably affected, though they are usually less severely affected than males.

Premutation allele carriers

Individuals with 55 to 200 CCG repeats are termed ‘premutation carriers’. Premutation carriers do not have fragile X syndrome, and may be entirely asymptomatic, but certain phenotypes are associated with premutation carrier status:

• fragile X tremor-ataxia syndrome (FXTAS): Around 40%–75% of male premutation carriers and 16%–20% of female premutation carriers will develop FXTAS in later life; and
• fragile X-associated primary ovarian insufficiency (FXPOI), leading to sub- or infertility and early menopause: Around 25% of female premutation carriers will experience FXPOI, which accounts for an estimated 3%–15% of all cases of primary ovarian insufficiency.

Intermediate allele carriers

Individuals with intermediate alleles are usually asymptomatic, but rare associations with neurological phenotypes and cases of FXPOI have been reported.

For information about testing, see Presentation: Child with suspected fragile X syndrome.

Fragile X syndrome is an X-linked condition. This means that:

• an affected female has a 50% (one-in-two) chance of passing on the condition to any offspring (either male or female);
• an affected male will pass on the condition to all his daughters, but none of his sons; and
• if a male proband has 200 or more repeats (a ‘full mutation’), the mother is heterozygous for either a premutation allele or a full mutation. She will require further evaluation and testing.

Fragile X syndrome has additional features to those listed here, which adds to the complexity of genomic counselling. Because it is a triplet-repeat expansion disorder, it may demonstrate anticipation (the tendency to become more severe over subsequent generations) in some families.

Premutation alleles are unstable, and may expand into the full mutation range in the offspring of a female premutation carrier. This expansion does not usually occur when male premutation carriers pass on the gene, although this is known to have occurred.

The likelihood of a premutation allele expanding to a full mutation in the offspring of a female carrier depends on its size and the number of AAG interruptions. This should be discussed with the clinical laboratory on a case-by-case basis.

There is also considerable variability in clinical presentation in females, due to variability in X-inactivation. It is therefore difficult to predict the extent to which a female child may be affected by the condition, which adds further layers of complexity to genomic counselling.

Management of children with fragile X syndrome is complex and should be delivered by a multidisciplinary team. For links to management guidelines, see the references section below.

For clinicians

• GeneReviews: FMR1 disorders
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Genetics and Genomics Education Centre: Fragile X (patient stories of living with fragile X syndrome)
• NHS England: National Genomic Test Directory
• OMIM: 300624 Fragile X syndrome
• U.S. National Library of Medicine: ClinicalTrials.gov database

References:

• Hagerman RJ and Hagerman P. ‘Fragile X-associated tremor/ataxia syndrome – features, mechanisms and management’. Nature Reviews Neurology 2016: volume 12, issue 7, pages 403–412. DOI: 10.1038/nrneurol.2016.82
• Rossetti R, Ferrari I, Bonomi M and others. ‘Genetics of primary ovarian insufficiency’. Clinical Genetics 2016: volume 91, issue 2, pages 183–198. DOI: 1111/cge.12921

For patients

• Fragile X Society
• National Genetics and Genomics Education Centre: Fragile X (patient stories of living with fragile X syndrome)