Annals of Laboratory Medicine

Korean Society for Laboratory Medicine (대한진단검사의학회)
권호 표지
DOI QR코드

DOI QR Code

Carrier Frequency and Prevalence of Citrin Deficiency in East Asians and Koreans Based on Comprehensive Analysis of Pathogenic SLC25A13 Variants

  • Mi-Ae Jang (Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Won Young Heo (Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Jong Kwon Lee (Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Jong-Won Kim (Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Sang-Mi Kim (Department of Laboratory Medicine, Chosun University Hospital, Chosun University School of Medicine) ;
  • Ja-Hyun Jang (Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Hyung-Doo Park (Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • Received : 2024.11.26
  • Accepted : 2025.05.07
  • Published : 2025.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Citrin deficiency is an autosomal recessive disorder caused by pathogenic variants in SLC25A13, presenting with various age-dependent clinical phenotypes and a broad spectrum of severity. However, few studies have examined the frequency and prevalence of citrin deficiency. We aimed to analyze the carrier frequency and disease prevalence in East Asian populations and Koreans. Methods: We comprehensively reviewed the literature and conducted a cross-sectional study to analyze genomic databases, including the Genome Aggregation Database (gnomAD), Korean Variant Archive (KOVA), and Tohoku Medical Megabank Organization (ToMMo), to identify pathogenic SLC25A13 variants in East Asian populations. A founder 3-kilobase (kb) insertion in intron 16 of SLC25A13 was investigated using whole-genome sequencing data from 681 Koreans with the Linux grep command. Results: Twenty-three pathogenic SLC25A13 variants were identified, with c.852_855del being the most common. Analysis of data from 17,501 East Asian individuals in the gnomAD and ToMMo databases revealed a carrier frequency of 1 in 62 people. Analysis of data from 7,214 individuals in the gnomAD and KOVA databases revealed a carrier frequency of 1 in 86, corresponding to an estimated disease prevalence of 1 in 29,502. c.1177+1G>A was identified as the most prevalent pathogenic variant in Koreans. The 3 kb insertion in intron 16 was detected in three out of 681 individuals, indicating a carrier frequency of 1 in 228. Conclusions: The high carrier frequency of citrin deficiency in East Asians highlights the need for enhanced genetic screening and counseling, particularly in Korea, providing a valuable reference for future studies on genetic diversity and pathogenic variants in this population.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (2021R1C1C1005725).

References

  1. Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 1999;22:159–63. https://doi.org/10.1038/9667
  2. Saheki T and Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet 2002;47:333–41. https://doi.org/10.1007/s100380200046
  3. Chen R, Wang XH, Fu HY, Zhang SR, Abudouxikuer K, Saheki T, et al. Different regional distribution of SLC25A13 mutations in Chinese patients with neonatal intrahepatic cholestasis. World J Gastroenterol 2013;19:4545–51. https://doi.org/10.3748/wjg.v19.i28.4545
  4. Lu YB, Kobayashi K, Ushikai M, Tabata A, Iijima M, Li MX, et al. Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. J Hum Genet 2005;50:338–46. https://doi.org/10.1007/s10038-005-0262-8
  5. Kikuchi A, Arai-Ichinoi N, Sakamoto O, Matsubara Y, Saheki T, Kobayashi K, et al. Simple and rapid genetic testing for citrin deficiency by screening 11 prevalent mutations in SLC25A13. Mol Genet Metab 2012;105:553–8. https://doi.org/10.1016/j.ymgme.2011.12.024
  6. Tabata A, Sheng JS, Ushikai M, Song YZ, Gao HZ, Lu YB, et al. Identification of 13 novel mutations including a retrotransposal insertion in SLC25A13 gene and frequency of 30 mutations found in patients with citrin deficiency. J Hum Genet 2008;53:534–45. https://doi.org/10.1007/s10038-008-0282-2
  7. Lin Y, Liu Y, Zhu L, Le K, Shen Y, Yang C, et al. Combining newborn metabolic and genetic screening for neonatal intrahepatic cholestasis caused by citrin deficiency. J Inherit Metab Dis 2020;43:467–77. https://doi.org/10.1002/jimd.v43.3
  8. Wongkittichote P, Sukasem C, Kikuchi A, Aekplakorn W, Jensen LT, Kure S, et al. Screening of SLC25A13 mutation in the Thai population. World J Gastroenterol 2013;19:7735–42. https://doi.org/10.3748/wjg.v19.i43.7735
  9. Oh SH, Lee BH, Kim GH, Choi JH, Kim KM, Yoo HW. Biochemical and molecular characteristics of citrin deficiency in Korean children. J Hum Genet 2017;62:305–7. https://doi.org/10.1038/jhg.2016.131
  10. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581:434–43. https://doi.org/10.1038/s41586-020-2308-7
  11. Kido J, Makris G, Santra S, Häberle J. Clinical landscape of citrin deficiency: a global perspective on a multifaceted condition. J Inherit Metab Dis 2024;47:1144–56. https://doi.org/10.1002/jimd.v47.6
  12. Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Källberg M, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 2016;32:1220–2. https://doi.org/10.1093/bioinformatics/btv710
  13. Demidov G, Park J, Armeanu-Ebinger S, Roggia C, Faust U, Cordts I, et al. Detection of mobile elements insertions for routine clinical diagnostics in targeted sequencing data. Mol Genet Genom Med 2021;9:e1807. https://doi.org/10.1002/mgg3.v9.12
  14. Chetruengchai W, Phowthongkum P, Shotelersuk V. Carrier frequency estimation of pathogenic variants of autosomal recessive and X-linked recessive Mendelian disorders using exome sequencing data in 1,642 Thais. BMC Med Genomics 2024;17:9.
  15. Xu X, He S, Li G, Wang Z, Lv L, Zhao Z, et al. Assessment the carrier frequency of monogenic diseases in populations requiring assisted reproductive technology. BMC Med Genomics 2024;17:214. https://doi.org/10.1186/s12920-024-01989-2
  16. Kim MJ, Kim SY, Lee JS, Kang S, Park LJ, Choi W, et al. Rapid targeted sequencing using dried blood spot samples for patients with suspected actionable genetic diseases. Ann Lab Med 2023;43:280–9. https://doi.org/10.3343/alm.2023.43.3.280
  17. Lee J, Lee J, Jeon S, Lee J, Jang I, Yang JO, et al. A database of 5305 healthy Korean individuals reveals genetic and clinical implications for an East Asian population. Exp Mol Med 2022;54:1862–71. https://doi.org/10.1038/s12276-022-00871-4
  18. Nagasaki M, Yasuda J, Katsuoka F, Nariai N, Kojima K, Kawai Y, et al. Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. Nat Commun 2015;6:8018. https://doi.org/10.1038/ncomms9018
  19. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, et al. HGVS Recommendations for the description of sequence variants: 2016 update. Hum Mutat 2016;37:564–9. https://doi.org/10.1002/humu.22981
  20. Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, et al. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet 2020;139:1197–207. https://doi.org/10.1007/s00439-020-02199-3
  21. Won D, Hwang JY, Shim Y, Byeon SH, Lee J, Lee CS, et al. In silico identification of a common mobile element insertion in exon 4 of RP1. Sci Rep 2021;11:13381. https://doi.org/10.1038/s41598-021-92834-4
  22. Song YZ, Zhang ZH, Lin WX, Zhao XJ, Deng M, Ma YL, et al. SLC25A13 gene analysis in citrin deficiency: sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China. PLoS One 2013;8:e74544. https://doi.org/10.1371/journal.pone.0074544
  23. Saheki T, Kobayashi K, Iijima M, Horiuchi M, Begum L, Jalil MA, et al. Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Mol Genet Metab 2004;81(S1):S20–6. https://doi.org/10.1016/j.ymgme.2004.01.006
  24. Lin J, Lin W, Lin Y, Peng W, Zheng Z. Clinical and genetic analysis of 26 Chinese patients with neonatal intrahepatic cholestasis due to citrin deficiency. Clin Chim Acta 2024;552:117617. https://doi.org/10.1016/j.cca.2023.117617
  25. Lin WX, Zhang ZH, Deng M, Cai XR, Song YZ. Multiple ovarian antral follicles in a preterm infant with neonatal intrahepatic cholestasis caused by citrin deficiency: a clinical, genetic and transcriptional analysis. Gene 2012;505:269–75. https://doi.org/10.1016/j.gene.2012.06.012
  26. Tanaka T, Nagao M, Tsutsumi H. Application of mutation analysis for the previously uncertain cases of adult-onset type II citrullinemia (CTLN2) and their clinical profiles. Tohoku J Exp Med 2002;198:89–97. https://doi.org/10.1620/tjem.198.89
  27. Tamamori A, Okano Y, Ozaki H, Fujimoto A, Kajiwara M, Fukuda K, et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Eur J Pediatr 2002;161:609–13. https://doi.org/10.1007/s00431-002-1045-2
  28. Hayasaka K, Numakura C, Toyota K, Kimura T. Treatment with lactose (galactose)-restricted and medium-chain triglyceride-supplemented formula for neonatal intrahepatic cholestasis caused by citrin deficiency. JIMD Rep 2012;2:37–44.
  29. Tang L, Chen L, Wang H, Dai L, Pan S. Case report: an adult-onset type II citrin deficiency patient in the emergency department. Exp Ther Med 2016;12:410–4. https://doi.org/10.3892/etm.2016.3298
  30. Treepongkaruna S, Jitraruch S, Kodcharin P, Charoenpipop D, Suwannarat P, Pienvichit P, et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among Thai infants. BMC Gastroenterol 2012;12:141. https://doi.org/10.1186/1471-230X-12-141
  31. Zeybek AC, Kiykim E, Zubarioglu T, Cansever MS, Ceylaner S, Erkan T. Citrin deficiency: an infant incidentally detected by phenylketonuria screening with a novel mutation in SLC25A13 gene. Genet Couns 2015;26:409–13.
  32. Zhang ZH, Lin WX, Deng M, Zhao XJ, Song YZ. Molecular analysis of SLC25A13 gene in human peripheral blood lymphocytes: marked transcript diversity, and the feasibility of cDNA cloning as a diagnostic tool for citrin deficiency. Gene 2012;511:227–34. https://doi.org/10.1016/j.gene.2012.09.049
  33. Wang K, Zou B, Chen F, Zhang J, Huang Z, Shu S. Case report: three novel variants on SLC25A13 in four infants with neonatal intrahepatic cholestasis caused by citrin deficiency. Front Pediatr 2023;11:1103877. https://doi.org/10.3389/fped.2023.1103877
  34. Kido J, Häberle J, Tanaka T, Nagao M, Wada Y, Numakura C, et al. Improved sensitivity and specificity for citrin deficiency using selected amino acids and acylcarnitines in the newborn screening. J Inherit Metab Dis 2024;47:1134-43. https://doi.org/10.1002/jimd.v47.6
  35. Okano M, Yasuda M, Shimomura Y, Matsuoka Y, Shirouzu Y, Fujioka T, et al. Citrin-deficient patient-derived induced pluripotent stem cells as a pathological liver model for congenital urea cycle disorders. Mol Genet Metab Rep 2024;40:101096.
  36. Vukovic T, Kuek LE, Yu B, Makris G, Häberle J. The therapeutic landscape of citrin deficiency. J Inherit Metab Dis 2024;47:1157-74. https://doi.org/10.1002/jimd.v47.6