Submission Details

The relationship between SARS2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 6, 2022. The SARS2 gene encodes mitochondrial seryl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of oxidative phosphorylation complex protein subunits.

The SARS2 gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2011 (PMID: 21255763). While various names have been given to the constellation of features seen in those with SARS2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the SARS2 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 nine unique variants, including eight missense variants and one splice-site variant. Nine probands were reported in nine publications between 2011-2022 (PMIDs: 21255763, 24034276, 33751860, 34407605, 35445976, 33972171, 27279129, 28716262, 31607746). The condition was first described in a consanguineous family from Palestine in a male proband and a similarly affected female cousin with early onset severe hyperuricemia, pulmonary hypertension, progressive renal failure, alkalosis, anemia, and elevated blood lactate levels (referred to by the acronym HUPRA syndrome for hyperuricemia, pulmonary hypertension, renal failure, and alkalosis). Subsequent publications have reported five additional cases with a consistently severe phenotype characterized by progressive kidney failure and pulmonary hypertension. In addition, there have been three reports of individuals with a predominant spastic paresis phenotype with infantile or childhood onset associated with a variable developmental delay and/or intellectual disability. No segregation data were available. Loss or altered function is proposed as the mechanism of disease. This gene-disease relationship is also supported by its known biochemical function that is shared with other genes associated with primary mitochondrial disease.

In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on June 6, 2022 (SOP Version 8).