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

Citrin deficiency (CD) is an autosomal recessive disorder caused by the absence or dysfunction of the mitochondrial transporter citrin, resulting from mutations in . The disease presents with age-dependent clinical manifestations: neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia by CD (FTTDCD), and an adult-onset form (formerly called Type II citrullinemia, CTLN2, recently renamed to "adolescent and adult citrin deficiency," AACD). We performed this study to compile known genotypes found in CD patients and investigate their impact on the clinical course. Through a nationwide survey in Japan as well as a literature review, we collected information regarding 68 genetic variants of a total of 345 patients with CD (285 NICCD, 19 post-NICCD, and 41 AACD). In this cohort, the pathogenic variants, arising from nonsense, insertion/deletion, and splice site mutations, are expected to have severe functional or biogenesis defects. Of 82 alleles in patients with AACD, the two most common variants, c.852_855del and c.1177+1G>A, accounted for 25 alleles (30.5%) and 15 alleles (18.3%), respectively. The c.852_855del variant, even when present as part of compound heterozygosity, often presented with hyperammonemia (≥ 180 μmol/L), cognitive impairment, short stature (< -2SD), liver cirrhosis, and pancreatitis, with some patients requiring liver transplantation. In conclusion, certain genotypes are particularly frequent, especially those that result in severely truncated citrin proteins with often a significant impact on the clinical outcome of the patient. The most prevalent variant is c.852_855del, which was found in 42% (128/304) of NICCD/post-NICCD cases and 49% (20/41) of AACD patients.