{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T16:49:48Z","timestamp":1770396588238,"version":"3.49.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"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                      Autosomal recessive polycystic kidney disease (ARPKD) is an inherited renal disorder characterized by multiple renal cysts. This study aimed to investigate the pathogenesis of\n                      <jats:italic>PKHD1<\/jats:italic>\n                      gene variants in a Chinese ARPKD pedigree and elucidate the mechanisms underlying the phenotypic heterogeneity in patients with\n                      <jats:italic>PKHD1<\/jats:italic>\n                      mutations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Clinical data and blood samples were collected from the proband and family members. Whole-exome sequencing (WES) and Sanger sequencing were performed. Conservative analysis and local secondary structure prediction of the mutation site were performed to evaluate the pathogenicity. The genotype-phenotype correlation of PKHD1 mutations was analyzed in combination with this pedigree.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A pediatric patient with ARPKD was identified. Ultrasonography revealed bilateral renal enlargement with multiple cysts, accompanied by hepatic fibrosis. WES identified a novel compound heterozygous variant in the\n                      <jats:italic>PKHD1<\/jats:italic>\n                      gene (c.5850_5851insTTCAT; p.Gly1951Phefs*25 and c.8710G &amp;gt; A; p.Glu2904Lys). Conservation analysis confirmed that both mutations occurred in conserved regions, indicating potential pathogenicity. Secondary structure prediction revealed that the p.Gly1951Phefs*25 frameshift mutation resulted in protein truncation and conformational changes, whereas the p.Glu2904Lys missense mutation caused drastic changes in amino acid polarity, impairing protein stability and function. Genotype-phenotype analysis of 605\n                      <jats:italic>PKHD1<\/jats:italic>\n                      mutations revealed a trend suggesting that hepatobiliary manifestations might present with less severe mutational burden compared to renal phenotypes, and mild homozygous missense mutations or heterozygous states may attenuate or eliminate renal phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study uncovered novel PKHD1 mutations in an ARPKD patient, expanding the pathogenic gene spectrum of ARPKD and providing insights for genetic counseling and prenatal diagnosis. Our findings also contribute to the understanding of genotype-phenotype correlations in PKHD1 mutation carriers and generate hypotheses regarding potential organ-specific thresholds for disease manifestation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1741795","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T06:40:40Z","timestamp":1770360040000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel compound heterozygous PKHD1 mutations in a Chinese ARPKD pedigree and analysis of genotype-phenotype correlations"],"prefix":"10.3389","volume":"13","author":[{"given":"Jie","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Emergency, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Second Dental Center, Ninth People\u2019s Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Emergency, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.cld.2022.01.009","article-title":"Polycystic kidney\/liver disease.","volume":"26","author":"Roediger","year":"2022","journal-title":"Clin Liver Dis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/s41572-018-0047-y","article-title":"Polycystic kidney disease.","volume":"4","author":"Bergmann","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1038\/ng.3871","article-title":"Mutations in Dzip1l, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease.","volume":"49","author":"Lu","year":"2017","journal-title":"Nat Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/ng833","article-title":"The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein.","volume":"30","author":"Ward","year":"2002","journal-title":"Nat Genet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"166348","DOI":"10.1016\/j.bbadis.2022.166348","article-title":"The genetics of Autosomal Recessive Polycystic Kidney Disease (ARPKD).","volume":"1868","author":"Goggolidou","year":"2022","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B6","doi-asserted-by":"publisher","first-page":"14633","DOI":"10.1111\/jcmm.16014","article-title":"The carboxy-terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC-activation.","volume":"24","author":"Dafinger","year":"2020","journal-title":"J Cell Mol Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/jhg.2016.58","article-title":"Expanding the mutation spectrum in 130 probands with ARPKD: identification of 62 novel PKHD1 mutations by sanger sequencing and MLPA analysis.","volume":"61","author":"Melchionda","year":"2016","journal-title":"J Hum Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.semcdb.2020.05.003","article-title":"Cilia and polycystic kidney disease.","volume":"110","author":"Ma","year":"2021","journal-title":"Semin Cell Dev Biol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1086\/340448","article-title":"PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats.","volume":"70","author":"Onuchic","year":"2002","journal-title":"Am J Hum Genet"},{"key":"B10","first-page":"543","article-title":"Polycystic kidney disease in neonates and infants. 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