Inheritance

X-linked dominant with maternal anticipation

Prevalence

 1-5 / 10 000

Source: ORPHA:908

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD

ClinGen Intellectual Disability and Autism, accessed 08.17.2023

Clinical Validity Scoring Notes and points

FMR1 was first reported in relation to X-linked fragile X syndrome in 1991 (Kremer et al., 1675488). The majority of cases are a result of an unstable expanded trinucleotide (CGG)n repeat sequence of greater than 200 repeats in the 5-prime untranslated region of FMR1; however, at least 10 unique variants (repeat expansion, missense, splice, nonsense, frameshift, insertion and large deletions) have been reported in humans. Other phenotypic presentations (Fragile X Tremor Ataxia Syndrome, Primary Ovarian Insufficiency) may be observed in individuals with FMR1 premutations (defined as 55-200 repeats). For the purposes of this curation, however, we have chosen to only evaluate evidence related to classic Fragile X syndrome. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 10 probands in 8 publications (1675488, 8490650, 8069307, 7670500, 21267007, 24448548, 25693964, 28176767).

More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached.

The mechanism for disease is hemizygous loss of function.

This gene-disease association is supported by animal models, expression studies and functional assays.

In summary, FMR1 is definitively associated with X-linked fragile X syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

This classification was approved by the ClinGen Intellectual Disability and Autism Working Group on 6/3/2019 (SOP Version 6).

Source: ClinGen Intellectual Disability and Autism, accessed 08.17.2023

Clinical Validity Points Total

18

Source: ClinGen Intellectual Disability and Autism, accessed 08.17.2023

Clinical Validity Classification

Definitive

Source: ClinGen Intellectual Disability and Autism, accessed 08.17.2023

Molecular Mechanism

Loss of function (due to truncating SNVs/indel or a triplet repeat expansion)

Triplet repeat expansions: CGG in the 5’UTR

• Normal: 5-44 repeats

• Intermediate alleles: 45-54 repeats

  • These do not cause FXS but 14% are unstable and may expand into the premutation range

• Premutation: 55-200 repeats

  • Presence of AGG interruptions reduce the risk of expansion to full mutation.

• Full mutation: >200 repeats

  • Presence of methylation is linked with increased severity. Alleles can be fully methylated or unmethylated, or mosaic for methylation.

  • For females with completely methylated alleles, approximately 50% have ID. For unmethylated or partial methylation the phenotype is highly variable.

Source: PMID: 20301558

LOF variants: From ClinGen ClinGen Intellectual Disability and Autism curation:

• ENST00000370475.9:c.373del p.Thr125LeufsTer? (listed as NC_000023.11:g.147928761del on ClinGen website). Reported de novo in individual with features of Fragile X.

• c.1021_1028delAATAATTCinsTATTGG p.(Asn341Tyrfs*7) PMID: 32688058, reported in a family with Fragile X syndrome.

• c.80C>A p.S27* reported in PMID: 21267007, in a patient with Fragile X syndrome

Penetrance

(list source/PMID)

FMR1 - Dependent on methylation status up to 100% for fully methylated alleles in males.

FXTAS - Low to Moderate, age related (17-75%)

POI - LOW (~20%)

Source: PMID: 20301558

Age of Onset

(list source/PMID)

Fragile X - early childhood

FXTAS and POI - Adulthood

Severity

Moderate

Clinical Features

Fragile X - caused by repeat expansions in the full mutation range

• Intellectual disability or DD

• Autism spectrum disorder, ADHD, anxiety

• Family history of FXTAS or POI

• medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Mitral valve prolapse or aortic root dilatation in adults.

• Physical features - Facial features (long face, prominent forehead, large ears, prominent jaws), macroorchidism

Fragile X Tremor Ataxia syndrome (FXTAS) - caused by repeat expansions in the premutation

• Neuropathic signs

  • FXTAS inclusions (characteristic ubiquitin-positive intranuclear inclusions within the nuclei of neurons and astrocytes)

• Radiologic signs:

  • MRI white matter lesions in middle cerebellar peduncles (MCP sign), cerebral white matter, or splenium of the corpus callosum

  • moderate-to-severe generalized brain atrophy

• Clinical signs

  • Intention tremor, cerebellar gait ataxia, Parkinsonism, short-term memory deficiency, executive function deficit, neuropathy in lower extremities

Primary Ovarian Insufficiency (POI) - caused by repeat expansions in the premutation range

Hypergonadotropic hypogonadism in women younger than age 40. POI is diagnosed when a woman has (1) experienced four to six months of amenorrhea (absent menses) and (2) has two serum menopausal level FSH values obtained at least one month apart.

Sources: PMID: 20301558

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

Triplet repeat expansions and small variants are known to cause disease, see molecular mechanism notes

Curation Summary

The FMR1 gene is associated with FMR1-related disorders which include Fragile X syndrome, Fragile X tremor ataxia syndrome (FXTAS), and premature ovarian failure.

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, 08.17.2023, https://broadinstitute.atlassian.net/browse/BCL-168