Submission Details

The relationship between NFU1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 11, 2023. NFU1 encodes a protein essential to the assembly of iron-sulfur (Fe-S) clusters.

NFU1 was first reported in relation to autosomal recessive primary mitochondrial disease in 2011 (PMID:21944046, although this case was first reported in 2001, PMID:11156534), in an infant who died at age one month due to respiratory failure in the setting of metabolic acidosis, hyperglycinemia and multiple organ failure. Tissue testing indicated a clear reduction in lipoate containing 2-oxoacid dehydrogenases (pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase) as well as defects in complexes I, II, and III which is characteristic of this Fe-S cluster defect. While various names have been given to the constellation of features seen in those with NFU1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NFU1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (two frameshift null variants, three missense variants, and one predicted missense variant resulting in aberrant splicing) in five probands from three publications (PMIDs: 22077971, 25918518, 25758857), although many additional cases (~35) are reported in the medical literature. The p.Gly208Cys variant appears to be a Basque founder variant. Affected individuals have a strikingly similar biochemical phenotype but variable severity of their clinical phenotype. Two general clinical phenotypes have been reported. One is an infantile onset, potentially fatal, lactic acidosis with leukoencephalopathy with or without pulmonary hypertension, optic atrophy, and/or cardiomyopathy. The second is an early childhood onset hereditary spastic paraplegia with leukoencephalopathy and regression. Affected individuals show a reduction in activities and amounts of lipoate containing enzymes as well as hyperglycinemia/hyperglycinuria (PMIDs: 22077971, 25918518, 25758857).

This gene-disease association is also supported by functional implication given protein interaction with other genes involved in Fe-S cluster assembly or lipoylation (PMID: 33007329). HeLa cell models and yeast cell models replicating similar biochemical defects seen in patients (PMID: 22077971) and functional deficiencies seen in patient cells (PMID:36256512) were also included in scoring.

In summary, there is definitive evidence to support the relationship between NFU1 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 July 11, 2023 (SOP Version 9).