FOXRED1

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0032624

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0032624

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *FOXRED1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2023. *FOXRED1* encodes FAD-dependent oxidoreductase domain-containing protein 1, a protein involved in the mid-late stages of mitochondrial complex I assembly that is predicted to also contain FAD and oxygen binding sites. *FOXRED1* was first reported in relation to autosomal recessive primary mitochondrial disease in 2010 (PMID:20858599), in a 10-year-old Iranian male with Leigh syndrome, hepatomegaly, and cardiomyopathy. Other associated features have been reported over time. While various names could be given to the constellation of features seen in those with *FOXRED1*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *FOXRED1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *FOXRED1* was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on October 14, 2019 (SOP v7), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique variants (four nonsense and frameshift variants resulting in truncation, four missense variants) in five probands across four publications (PMIDs: 20858599, 20818383, 30723688, 33613441). Features in affected individuals include LSS, cystic leukoencephalopathy, epilepsy, hepatomegaly, cardiomyopathy, pulmonary hypertension, renal tubular acidosis, and optic atrophy. Lactic acidosis is also seen. This gene-disease association is also supported by its known biochemical function shared with other complex I subunits and assembly factors, functional alteration in patient cells, siRNA knockdown in mouse neurons, and rescue of complex I assembly in HEK293T cells (PMIDs: 25678554, 28797839, 30392038, 22200994). In summary, there is definitive evidence to support the relationship between *FOXRED1* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 21, 2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between FOXRED1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 14, 2019. Variants in FOXRED1 were first reported in humans with Leigh syndrome spectrum as early as 2010 (PMID: 20818383). Four unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Two probands with confirmed FOXRED1 mutations demonstrating a Leigh syndrome spectrum phenotype have been reported in 2 publications (PMIDs: 26022995, 20818383) to reach a case-level evidence score of 4. This gene-disease association is further supported by FOXRED1’s protein interaction and shared function with other genes associated with Leigh syndrome spectrum, mitochondrial alterations in patient cell lines, and a FOXRED1 mouse model exhibiting a neuropathological and behavioral phenotype, reaching an experimental score of 5 pts. In summary, there is moderate evidence to support the relationship between FOXRED1 and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 14, 2019 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0100224

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.