Submission Details

The relationship between LRPPRC and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 20, 2024. LRPPRC encodes an important post-transcriptional regulator of mitochondrial gene expression and coordinates mitochondrial translation.

LRPPRC was first reported in relation to autosomal recessive primary mitochondrial disease in 2003 (PMID: 12529507), in individuals first described in 1993 (PMID: 8392291). While various names have been given to the constellation of features seen in those with LRPPRC-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the LRPPRC phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, LRPPRC was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on December 9, 2019 (SOP V7), with a final classification of Definitive. This current curation for the association with primary mitochondrial disease includes the cases included in the LSS curation.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six variants [two missense variants including NM_133259.4:c.1061C>T (p.Ala354Val) that is a founder variant from the French Canadian population, one in-frame deletion, one intronic variant, and two splice site variants) in 13 probands from five publications (PMIDs: 12529507, 21266382, 26510951, 38046674, 32972427). Clinical features in affected individuals include LSS, severe lactic acidosis, severe developmental delay, acute neurodegeneration, brain malformations, feeding difficulty, dysphagia, hypoglycemia, cardiomyopathy, and dysmorphic features. Complex IV deficiency is seen in muscle and skin fibroblasts. There have been reports of variants in LRPPRC being associated with primary ovarian insufficiency, however currently conclusive evidence is lacking to support this association (PMIDs: 32962729, 28284481).

The mechanism of disease is loss of function This gene-disease association is also supported by its known biochemical function of LRPPRC, functional alteration in patient and non-patient cells, and fruit fly and mouse model systems (PMIDs: 26510951, 25835550, 20677761, 25428350, 28575497, 22045337, 22045337).

In summary, there is definitive evidence to support the relationship between LRPPRC 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 June 20, 2024 (SOP Version 10).