Deciphering the Mutational Background in Citrin Deficiency Through a Nationwide Study in Japan and Literature Review

Area of Science:

• Genetics
• Metabolic Disorders
• Molecular Biology

Background:

• Citrin deficiency (CD) is an autosomal recessive disorder linked to mutations in the SLC25A13 gene, affecting the mitochondrial citrin transporter.
• CD manifests with age-dependent phenotypes including neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adolescent/adult-onset forms (AACD).

Purpose of the Study:

• To compile known genotypes in CD patients.
• To investigate the impact of specific SLC25A13 genotypes on the clinical course of citrin deficiency.

Main Methods:

• A nationwide survey in Japan and a literature review were conducted.
• Data from 345 CD patients (285 NICCD, 19 post-NICCD, 41 AACD) with 68 identified genetic variants were analyzed.

Main Results:

• The c.852_855del variant is the most prevalent, found in 42% of NICCD/post-NICCD and 49% of AACD patients.
• This variant, even in compound heterozygosity, is associated with severe outcomes like hyperammonemia, cognitive impairment, short stature, liver cirrhosis, and pancreatitis, sometimes necessitating liver transplantation.
• Two common AACD variants, c.852_855del and c.1177+1G>A, accounted for over 48% of alleles in this patient group.

Conclusions:

• Certain SLC25A13 genotypes are frequent in CD patients and significantly impact clinical outcomes.
• Genotypes leading to severely truncated citrin proteins are particularly associated with adverse clinical manifestations.
• The c.852_855del variant is a major determinant of disease severity across different CD phenotypes.