Submission Details

The relationship between FBXL4 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 23, 2024. FBXL4 encodes F-box and leucine-rich repeat protein 4. This protein forms a ubiquitin ligase complex (SKP1–CUL1–F-box protein) that targets mitophagy receptors for degradation, thereby restricting steady-state mitophagy. Pathogenic variants in FBXL4 result in inability to mediate turnover of these receptors resulting in increased basal mitophagy (PMIDs: 37161784, 37568009)

FBXL4 was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMIDs: 23993193, 23993194). While various names have been given to the constellation of features seen in those with FBXL4-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the FBXL4 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, FBXL4 was previously curated by this GCEP on April 20, 2020 (SOP Version 7) as having a Definitive association with autosomal recessive Leigh syndrome spectrum (LSS). This current curation for the association with primary mitochondrial disease includes the seven probands included in the LSS curation.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 13 variants (eight missense, one frameshift, two termination, and two variants predicted to impact splicing) in 11 probands from three publications (PMIDs: 23993193, 23993194, 34602956). More cases are reported in the medical literature as it appears there have been more than 50 variants reported in over 100 affected individuals to date, but the maximum case level scoring was reached for this curation. Age of onset is variable and ranges from prenatally to the first months of life. Clinical features in affected individuals include LSS, leukoencephalopathy, lactic acidosis, intellectual disability, seizures, movement disorder, ataxia, renal tubular acidosis, swallow dysfunction, failure to thrive, cataracts, abnormal sleep, hypertrophic cardiomyopathy, and dysmorphic features. Muscle biopsies show mitochondrial respiratory chain enzyme deficiencies and mitochondrial DNA depletion.

Of note, this gene was also reviewed by the Prenatal Gene Curation Expert Panel. The prenatal presentation is part of the primary mitochondrial disease phenotype spectrum. Clinical findings have been diagnosed prenatally in at least five probands in three publications (PMIDs: 27182039 27099744, 36411461) via ultrasounds and magnetic resonance imaging. These probands had missense and nonsense variants. The prenatal phenotype includes polyhydramnios, intrauterine growth restriction, low birth weight, and cardiac ventricular wall thickening consistent with cardiomyopathy. Central nervous system findings include cerebellar hypoplasia, enlarged cisterna magna, microcephaly, and mild ventriculomegaly with small periventricular cysts. Decreased fetal movements have also been reported.

The mechanism of disease is loss of function. This gene-disease association is also supported by functional alteration in patient cells and animal models including worm, zebrafish, and mice (PMIDs: 23993193, 23993194, 31969900, 35881484, 32525278).

In summary, there is definitive evidence to support the relationship between FBXL4 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 23, 2024 (SOP Version 10).