Submission Details

SLC25A13/citrin was first reported in relation to citrullinemia type 2 (CTLN2) in 1999 (Kobayashi K et al. PMID: 10369257) and in relation to neonatal intrahepatic cholestasis due to citrin deficiency (NICCD) in 2000 (Ohura T et al. PMID: 11281457). At least 10 unique variants, most of which are null or missense, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 6 probands with citrullinemia type 2 in 4 publications (PMIDs: 18367750, 10369257, 19036621, 18392553) as well as in 4 publication describing at least 5 probands with neonatal intrahepatic cholestasis (PMIDs: 21914561, 11343052, 11343053, 31607264). At least one proband with neonatal intrahepatic cholestasis developed citrullinemia type 2 later in life (Tomomasa et al. PMID 11343053). All of these probands share the common biochemical abnormality of elevated plasma citrulline. The mechanism for disease is biallelic loss of function, with significantly reduced or absent glutamate transport into and aspartate transport out of mitochondria which deprives argininosuccinate synthetase of a substrate leading to accumulation of citrulline and ammonia. This gene-disease association is also supported by the protein's biological function and functional studies recombinant proteins and complementation studies in yeast which demonstrated that mutant proteins have significantly impacted carrier activity when compared to the wild-type. In summary, SLC25A13/citrin is definitively associated with autosomal recessive citrullinemia type 2. This has been repeatedly demonstrated in the clinical diagnostic setting and has been upheld over time.