FXN Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note):
Disease | Friedreich ataxia |
|---|---|
Inheritance | Autosomal recessive |
Prevalence | 1-9 / 100 000 Source: ORPHA:95 |
Rapid or full curation? | Rapid Full |
ClinGen Hypertrophic Cardiomyopathy GCEP, accessed 08.17.2023 | |
Clinical Validity Scoring Notes and points | The FXN gene is associated with Friedreich ataxia, the most common form of inherited ataxia (Burk 2017, PMID: 28405347; Payne and Wagner 2012, PMID: 22764179). Friedreich ataxia is an autosomal recessive disorder characterized by progressive muscle weakness and ataxia, dysarthria, scoliosis, and cardiomyopathy. Homozygous inheritance of a GAA trinucleotide expansion within intron 1 of FXN accounts for 95% of Friedrich ataxia cases, while 5% of cases are due to compound heterozygous mutations including missense and nonsense mutations in FXN on one allele and the GAA trinucleotide repeat on the second allele (Burk 2017; PMID: 28405347; Delatycki 2000, PMID: 10633128). Friedreich ataxia was first described in 1863, by Nikolaus Friedreich, but it was not until 1996 that Campuzano and colleagues (PMID: 8596916) identified FXN as the causative gene responsible for Friedreich ataxia (Schulz 2013, PMID: 24024236). Many more cases are reported in the literature but the maximum score for genetic evidence (12 pts) has already been reached. Of note, FXN is a gene that is highly conserved from bacteria to mammals, and haplotype analysis has revealed a common ancestor originating from the Franco-Cantabrian ice age refuge (reviewed in Burk 2017, PMID: 28405347). The mechanism for disease is loss of function, as the GAA trinucleotide expansion results in the loss of FXN transcript due to epigenetic regulation. Loss of FXN (frataxin) results in reduced iron homeostasis within mitochondria, and results in mitochondrial dysfunction. This gene-disease association is supported by the function of the gene product, animal models, and rescue experiments. In summary, FXN is definitively associated with Friedreich ataxia. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Data on the occurrence of hypertrophic cardiomyopathy (HCM) or cardiomyopathy in individuals with Friedreich ataxia was collected by the Hypertrophic Cardiomyopathy Gene Curation Committee (subgroup of the Cardiovascular Working Group). Loss of FXN results in the development of cardiomyopathy in ~92% of patients with Friedreich ataxia, and for 60% of these individual’s heart failure is the primary cause of death within the third to fifth decade of life (Payne and Wagner 2012, PMID: 22764179). The cardiomyopathy involved in Friedreich ataxia includes left ventricular hypertrophy, impaired myocardial perfusion, and arrhythmias. The cardiac hypertrophy observed in Friedreich ataxia was noted to differ from hypertrophic cardiomyopathy, as it is caused by increased proliferation of dysfunctional mitochondria within the cardiomyocytes which can ultimately lead to a dilated left ventricle and reduced ejection fraction (Payne and Wagner 2012, PMID: 22764179; Payne and Perverill 2012; PMID: 22373590). Source: ClinGen Hypertrophic Cardiomyopathy GCEP, accessed 08.17.2023 |
Clinical Validity Points Total | 18 Source: ClinGen Hypertrophic Cardiomyopathy GCEP, accessed 08.17.2023 |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive Source: ClinGen Hypertrophic Cardiomyopathy GCEP, accessed 08.17.2023 |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function (due to triplet repeat expansion or small variants) Triplet repeat expansion - GAA repeat within intron 1 of FXN
Small variants
Source: PMID: 17703324, ClinGen Hypertrophic Cardiomyopathy GCEP, accessed 08.17.2023
|
Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) | Complete (full mutation expansions), possibly incomplete/reduced for borderline alleles Source: 20301458 |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Pediatric - Late Adulthood (dependent on repeat length) Source: 20301458, 35332317 |
Severity | Moderate |
Clinical Features |
Sources: 20301458, 35332317 |
HPO Terms | HP:0001251Ataxia Gait disturbance HP:0001288 Reduced tendon reflexes HP:0001315 Dysarthria HP:0001260 Dysphagia HP:0002015 Impaired vibration sensation in the lower limbs HP:0002166 Impaired proprioception HP:0010831 Spasticity HP:0001257 Muscle weakness HP:0001324 Scoliosis HP:0002650 Cerebellar atrophy HP:0001272 Atrophy of the spinal cord HP:0006827 Hypertrophic cardiomyopathy HP:0001639 Diabetes mellitus HP:0000819 Glucose intolerance HP:0001952 Sensorineural hearing impairment HP:0000407 Optic neuropathy HP:0001138 |
Gene SOPs & Notes | Pathogenic variant spectrum includes small variants, copy number variants, and triplet repeat expansions. |
Curation Summary | The FXN gene is associated with autosomal recessive Friedreich ataxia, which is characterized by progressive ataxia and other features including dysarthria, muscle weakness, scoliosis, hypertrophic cardiomyopathy, diabetes mellitus, sensorineural hearing loss and optic neuropathy (PMID: 20301458, 35332317). It is caused by sequence and copy number variants, as well as short tandem repeat expansions in intron 1 of the gene. Severity and age of onset have been linked to repeat length, with larger repeats associated with increased severity and earlier age of onset (PMID: 20301458, 35332317). |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza, 08.21.2023 https://broadinstitute.atlassian.net/browse/BCL-168 |