{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T20:34:03Z","timestamp":1768336443878,"version":"3.49.0"},"reference-count":11,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Progressive liver cirrhosis in pediatric patients characterized by clinical and genetic variability. Infantile cirrhosis caused by biallelic variants in the\n                      <jats:italic>FOCAD<\/jats:italic>\n                      gene is an extremely rare multi-system disorder leading to the progressive liver dysfunction. A small number of patients with limited survival were described so far, and any new clinical observation can provide a new insight for complete phenotypic spectrum and perspectives on available treatment to meet patient\u2019s needs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed clinical, instrumental, histological and laboratory evaluation of the family with patient (male, 3 y.o.) with progressive liver cirrhosis and apparently healthy parents. Genetic study was performed using whole-exome sequencing. Validation of the rare variant found on WES and cascade familial screening were performed by capillary Sanger sequencing. Functional validation included RNA analysis from patient-derived fibroblasts and\n                      <jats:italic>in silico<\/jats:italic>\n                      protein modeling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The patient exhibited an expanded phenotype including microcephaly, macrotia and neutropenia. Genetic testing revealed a novel homozygous\n                      <jats:italic>FOCAD<\/jats:italic>\n                      splice-site variant NM_001375570.1:c.1455\u202f+\u202f1G\u202f&amp;gt;\u202fT\n                      <jats:italic>FOCAD<\/jats:italic>\n                      (NM_001375570.1):c.1455\u202f+\u202f1G\u202f&amp;gt;\u202fT affecting RNA splicing with in-frame deletion of 36 nucleotides. Aberrant protein lacks 12 aminoacids (p.Thr475_Val486del) resulting in loss of two conserved\n                      <jats:italic>\u03b1<\/jats:italic>\n                      -helices. Structural modeling predicted impaired protein stability. At 25\u202fmonths, the patient underwent a living-donor liver transplantation with a good clinical result, and favorable outcome in 1\u202fyear post-liver transplant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Canonic splice site variant NM_001375570.1:c.1455\u202f+\u202f1G\u202f&amp;gt;\u202fT\n                      <jats:italic>FOCAD<\/jats:italic>\n                      (NM_001375570.1):c.1455\u202f+\u202f1G\u202f&amp;gt;\u202fT realizes through in-frame deletion of 12 amimoacids (p.Thr475_Val486del) of the FOCAD protein with detectable expression in patient-derived cells. Homozygous carrier of this pathogenic variant exhibits progressive hepatic failure expanded with neutropenia. Liver transplantation had a good long-term result, and can be considered as a promising surgical approach for patients with\n                      <jats:italic>FOCAD<\/jats:italic>\n                      -related infantile cirrhosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2025.1680857","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T14:00:02Z","timestamp":1768312802000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel homozygous splice-site variant in the FOCAD gene causing infantile liver cirrhosis and neutropenia: expanding disease phenotype and successful surgical treatment"],"prefix":"10.3389","volume":"12","author":[{"given":"Ekaterina","family":"Nuzhnaya","sequence":"first","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Zaklyazminskaya","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, NRCS, The Federal Agency for Scientific Organizations","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viktoriia","family":"Zabnenkova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darya","family":"Akimova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evgeny","family":"Tatarsky","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lana","family":"Dzik","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, NRCS, The Federal Agency for Scientific Organizations","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrey","family":"Surkov","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, NRCS, The Federal Agency for Scientific Organizations","place":["Moscow, Russia"]},{"name":"Pirogov Russian National Research Medical University","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Zhurkova","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, NRCS, The Federal Agency for Scientific Organizations","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrey","family":"Filin","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, NRCS, The Federal Agency for Scientific Organizations","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksej","family":"Metelin","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, NRCS, The Federal Agency for Scientific Organizations","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Arakelyan","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, NRCS, The Federal Agency for Scientific Organizations","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viktoriya","family":"Savina","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, NRCS, The Federal Agency for Scientific Organizations","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arshak","family":"Babayan","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, NRCS, The Federal Agency for Scientific Organizations","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikhail","family":"Skoblov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Semenova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics","place":["Moscow, Russia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1016\/S0140-6736(21)01374-X","article-title":"Liver cirrhosis","volume":"398","author":"Gin\u00e8s","year":"2021","journal-title":"Lancet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1055\/s-0040-1715119","article-title":"Wolman\u2019s disease: a rare cause of infantile cholestasis and cirrhosis","volume":"11","author":"Menon","year":"2020","journal-title":"J Pediatr Genet"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.humpath.2019.09.015","article-title":"Etiology of cirrhosis in the young","volume":"96","author":"Olave","year":"2019","journal-title":"Hum Pathol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1038\/s41588-022-01120-0","article-title":"Loss of FOCAD, operating via 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pathway","volume":"37","author":"Liu","year":"2020","journal-title":"Redox Biol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e93764","DOI":"10.7759\/cureus.93764","article-title":"FOCAD gene defect resulting in rapidly progressing neonatal liver cirrhosis requiring transplant","volume":"17","author":"Raja","year":"2025","journal-title":"Cureus"}],"container-title":["Frontiers in 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