FARS2

Inheritance Pattern: AR

Disease ID:MONDO:0014882

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013986

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0005066

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between FARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 14, 2019. The FARS2 gene encodes mitochondrial phenylalanyl-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 FARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22499341). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants identified in four cases from three publications (PMIDs: 22499341, 27549011, 29126765). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in Alpers syndrome and other mitochondrial diseases which will be assessed separately. This gene-disease association is also supported by expression data, biochemical function data, and functional alterations in patient cells (PMIDs: 27977873, 26553276, 29126765). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 14, 2019 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0014882

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013986

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013986

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014882

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *FARS2* and *FARS2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 16, 2024. The *FARS2* gene encodes mitochondrial phenylalanine-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 protein subunits of oxidative phosphorylation complexes I, III, IV, and V. The *FARS2* gene was first reported in relation to autosomal recessive *FARS2*-related primary mitochondrial disease in 2012 (PMID: 22499341). *FARS2* has been associated with two disease entities to date; combined oxidative phosphorylation deficiency 14 [OMIM# 614946] and spastic paraplegia 77, autosomal recessive [OMIM# 617046]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *FARS2*-related primary mitochondrial disease. Of note, *FARS2* was first curated by this Expert Panel 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 *FARS2*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 10 unique variants (nine missense, one deletion) identified in 10 unrelated cases from six publications (PMIDs: 22499341, 27549011, 29126765, 22833457, 27095821, 30177229), although more than 40 affected individuals have been reported to date. Age of onset varies from neonatal period to childhood and outcomes are variable. There are two predominant phenotypes (early onset encephalopathy and later onset spastic paraplegia) however there is overlap in some cases. Several cases have features consistent with Alpers syndrome and/or Leigh syndrome spectrum disorder. Additional medical concerns include seizures, infantile spasms, epilepsia partialis continua (EPC), microcephaly, developmental delay and regression, hypotonia, spasticity, muscle weakness, myoclonus, neuropathy, tremor, dystonic movements, poor growth, vomiting, constipation, cortical blindness, anemia, thrombocytopenia, and lactic acidosis. Muscle biopsies were variable and some showed mitochondrial respiratory chain complex enzyme deficiencies. Brain imaging is similarly variable and includes cerebral and cerebellar atrophy and abnormal signal intensities in the deep cerebellar white matter and basal ganglia. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration studies in patient cells (PMID: 33168986), and a *Drosophila melanogaster* model (PMID: 36205831). In summary, there is definitive evidence to support the relationship between *FARS2* and autosomal recessive *FARS2*-related 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 December 16, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0016387

Submitter: PanelApp Australia