FASTKD2

Inheritance Pattern: AR

Disease ID:MONDO:0015632

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0030020

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *FASTKD2 *and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 21, 2022. The *FASTKD2* gene encodes the FAST kinase domain-containing protein 2, an RNA-binding protein required for mitochondrial RNA processing and translation. The *FASTKD2* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18771761). While various names have been given to the constellation of features seen in those with *FASTKD2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *FASTKD2* 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 eight unique variants reported in six cases from four publications (PMIDs: 18771761, 31944455, 28499982, 34234304). Insufficient clinical data were available to include two additional reports in this curation (PMIDs: 30831263, 25497598). Variants included four nonsense, two frameshift, and one missense. The condition was first described in two similarly affected siblings from consanguineous Bedouin family who presented with a severe encephalomyopathy including asymmetrical brain atrophy, developmental delay, fixed contractures, bilateral optic atrophy and elevated serum lactate. A subsequent publication reported three additional probands with a similar early onset, severe, multisystem disorder (PMID: 31944455). Two cases with a later onset disease have also been reported in the literature. One case was a male with syndrome resembling mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and an onset of disease at 15 years, the other a female with an onset of a cerebellar ataxia phenotype at the age of 42 years (PMIDs: 28499982, 34234304). This gene-disease relationship is also supported by a biochemical function (mitochondrial RNA processing for translation) shared with other genes associated with primary mitochondrial disease and biochemical evidence from patient derived lymphoblast cell lines (PMID: 31944455). In summary, there is definitive evidence to support the relationship between *FASTKD2* 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 July 21, 2022 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0030020

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0015632

Submitter: PanelApp Australia