SLC25A13 – Neonatal Intrahepatic Cholestasis due to Citrin Deficiency

Neonatal intrahepatic cholestasis due to citrin deficiency (MONDO:0011601) is caused by biallelic variants in SLC25A13, encoding the mitochondrial aspartate–glutamate carrier citrin. Affected infants present with prolonged neonatal jaundice, intractable cholestasis, hepatic steatosis, hypoglycemia, and coagulopathy.

The overall clinical validity of this gene–disease association is Definitive. Over 500 probands from diverse ethnic backgrounds harbor biallelic SLC25A13 pathogenic variants, with consistent phenotype and segregation of variants in multiple sibships. Experimental concordance across expression studies and animal models further supports causality.

SLC25A13 deficiency follows autosomal recessive inheritance. Cases include two Malaysian siblings with compound heterozygous frameshift variants c.851_855del (p.Arg284HisfsTer6) and IVS16ins3kb, confirmed by mutational analysis in both siblings (PMID:20200759). The variant spectrum comprises over 100 unique alleles, including recurrent frameshift, splice‐site, missense, and large deletion/insertion mutations.

Functional studies demonstrate that citrin loss impairs mitochondrial aspartate transport and the malate–aspartate shuttle. Ctrn‐knockout mice exhibit reduced ureagenesis and gluconeogenesis (PMID:14701727). Yeast AGC1‐deficient assays confirm pathogenicity of p.Val264Ile (c.790G>A) and other missense alleles (PMID:25216257). PBL cDNA cloning elucidates aberrant splicing and large deletion transcripts, validating diagnostic cDNA-based approaches (PMID:27127784).

No credible evidence refutes the SLC25A13–NICCD link, and alternative phenotypes such as adult-onset citrullinemia type II represent later manifestations of the same genetic etiology. The concordant genetic and mechanistic data firmly establish a Definitive association.

Key take-home: Genetic testing of SLC25A13 should be integrated into the evaluation of neonates with unexplained cholestatic jaundice to enable early dietary intervention and avoid invasive diagnostics.

References

• Singapore medical journal • 2010 • Neonatal intrahepatic cholestasis caused by citrin deficiency in two Malaysian siblings: outcome at one year of life. PMID:20200759
• European journal of medical genetics • 2014 • Inspissated bile syndrome in an infant with citrin deficiency and congenital anomalies of the biliary tract and esophagus: identification and pathogenicity analysis of a novel SLC25A13 mutation with incomplete penetrance. PMID:25216257
• BioMed research international • 2016 • Identification of a Large SLC25A13 Deletion via Sophisticated Molecular Analyses Using Peripheral Blood Lymphocytes in an Infant with Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD): A Clinical and Molecular Study. PMID:27127784
• Molecular and cellular biology • 2004 • Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. PMID:14701727

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