{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T05:57:38Z","timestamp":1773035858545,"version":"3.50.1"},"reference-count":84,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T00:00:00Z","timestamp":1692403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Radboud Institute for Molecular Life Sciences\/Research Institute","award":["RIMLS 2018-009a"],"award-info":[{"award-number":["RIMLS 2018-009a"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Protein-truncating variants in \u03b1-1,3-glucosyltransferase (ALG8) are a risk factor for a mild cystic kidney disease phenotype. The association between these variants and liver cysts is limited. We aim to identify pathogenic ALG8 variants in our cohort of autosomal dominant polycystic liver disease (ADPLD) individuals. In order to fine-map the phenotypical spectrum of pathogenic ALG8 variant carriers, we performed targeted ALG8 screening in 478 ADPLD singletons, and exome sequencing in 48 singletons and 4 patients from two large ADPLD families. Eight novel and one previously reported pathogenic variant in ALG8 were discovered in sixteen patients. The ALG8 clinical phenotype ranges from mild to severe polycystic liver disease, and from innumerable small to multiple large hepatic cysts. The presence of &lt;5 renal cysts that do not affect renal function is common in this population. Three-dimensional homology modeling demonstrated that six variants cause a truncated ALG8 protein with abnormal functioning, and one variant is predicted to destabilize ALG8. For the seventh variant, immunostaining of the liver tissue showed a complete loss of ALG8 in the cystic cells. ALG8-associated ADPLD has a broad clinical spectrum, including the possibility of developing a small number of renal cysts. This broadens the ADPLD genotype\u2013phenotype spectrum and narrows the gap between liver-specific ADPLD and kidney-specific ADPKD.<\/jats:p>","DOI":"10.3390\/genes14081652","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T01:38:31Z","timestamp":1692581911000},"page":"1652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel \u03b1-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7583-6991","authenticated-orcid":false,"given":"Melissa M.","family":"Boerrigter","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Research Institute for Medical Innovation, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren\u00e9 H. M.","family":"te Morsche","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Research Institute for Medical Innovation, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanka","family":"Venselaar","sequence":"additional","affiliation":[{"name":"Center for Molecular and Biomolecular Informatics, Research Institute for Medical Innovation, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikki","family":"Pastoors","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Research Institute for Medical Innovation, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja M.","family":"Geerts","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Ghent University Hospital, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Hoorens","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ghent University Hospital, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8027-3073","authenticated-orcid":false,"given":"Joost P. H.","family":"Drenth","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Research Institute for Medical Innovation, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.jhep.2017.11.024","article-title":"Clinical management of polycystic liver disease","volume":"68","author":"Banales","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1146\/annurev-pathol-042320-121247","article-title":"Polycystic Liver Disease: Advances in Understanding and Treatment","volume":"17","author":"Masyuk","year":"2022","journal-title":"Annu. Rev. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41575-022-00617-7","article-title":"Genetics, pathobiology and therapeutic opportunities of polycystic liver disease","volume":"19","author":"Olaizola","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"eaat9819","DOI":"10.1126\/science.aat9819","article-title":"Structure of the human PKD1-PKD2 complex","volume":"361","author":"Su","year":"2018","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109490","DOI":"10.1016\/j.cellsig.2019.109490","article-title":"Polycystin 2: A calcium channel, channel partner, and regulator of calcium homeostasis in ADPKD","volume":"66","author":"Brill","year":"2020","journal-title":"Cell. Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1681\/ASN.2022010053","article-title":"Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease","volume":"33","author":"Padhy","year":"2022","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"109640","DOI":"10.1016\/j.cellsig.2020.109640","article-title":"Polycystins as components of large multiprotein complexes of polycystin interactors","volume":"72","author":"Hardy","year":"2020","journal-title":"Cell. Signal."},{"key":"ref_8","unstructured":"Masyuk, T., Masyuk, A., and LaRusso, N. (2020). The Liver, Wiley-Blackwell."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"135","DOI":"10.2147\/HMER.S377530","article-title":"Polycystic Liver Disease: Pathophysiology, Diagnosis and Treatment","volume":"14","author":"Norcia","year":"2022","journal-title":"Hepat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"846877","DOI":"10.3389\/fgene.2022.846877","article-title":"Molecular Mechanisms of Isolated Polycystic Liver Diseases","volume":"13","author":"Yu","year":"2022","journal-title":"Front. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Reiterov\u00e1, J., and Tesa\u0159, V. (2022). Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063317"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1053\/j.gastro.2011.08.004","article-title":"Secondary, somatic mutations might promote cyst formation in patients with autosomal dominant polycystic liver disease","volume":"141","author":"Janssen","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1038\/ejhg.2016.97","article-title":"Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes","volume":"24","author":"Wills","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nrgastro.2017.69","article-title":"Genetics: Novel causative genes for polycystic liver disease","volume":"14","author":"Perugorria","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104160","DOI":"10.1016\/j.ejmg.2021.104160","article-title":"Polycystic liver disease genes: Practical considerations for genetic testing","volume":"64","author":"Boerrigter","year":"2021","journal-title":"Eur. J. Med. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S1665-2681(19)31406-1","article-title":"Polycystic liver disease: A clinical review","volume":"11","author":"Chandok","year":"2012","journal-title":"Ann. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.cgh.2016.03.008","article-title":"Polycystic Liver Disease: The Benefits of Targeting cAMP","volume":"14","author":"Larusso","year":"2016","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1111\/liv.14986","article-title":"Estrogens in polycystic liver disease: A target for future therapies?","volume":"41","author":"Aapkes","year":"2021","journal-title":"Liver Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1159\/000450989","article-title":"Bile Acids in Polycystic Liver Diseases: Triggers of Disease Progression and Potential Solution for Treatment","volume":"35","author":"Perugorria","year":"2017","journal-title":"Dig. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1136\/gutjnl-2013-305281","article-title":"Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases","volume":"63","author":"Urribarri","year":"2014","journal-title":"Gut"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1006427","DOI":"10.3389\/fphys.2022.1006427","article-title":"Non-coding RNAs as potential biomarkers and therapeutic targets in polycystic kidney disease","volume":"13","author":"Zheng","year":"2022","journal-title":"Front. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1002\/ueg2.12126","article-title":"Inhibition of NAE-dependent protein hyper-NEDDylation in cystic cholangiocytes halts cystogenesis in experimental models of polycystic liver disease","volume":"9","author":"Olaizola","year":"2021","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.jhep.2020.09.010","article-title":"Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models","volume":"74","author":"Olaizola","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1002\/hep.29577","article-title":"Cholangiocyte autophagy contributes to hepatic cystogenesis in polycystic liver disease and represents a potential therapeutic target","volume":"67","author":"Masyuk","year":"2018","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1111\/liv.14485","article-title":"Proteostasis disturbances and endoplasmic reticulum stress contribute to polycystic liver disease: New therapeutic targets","volume":"40","author":"Rodrigues","year":"2020","journal-title":"Liver Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"109509","DOI":"10.1016\/j.cellsig.2019.109509","article-title":"Epigenetics and cell cycle regulation in cystogenesis","volume":"68","author":"Li","year":"2020","journal-title":"Cell. Signal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1016\/j.ajhg.2022.06.013","article-title":"Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis","volume":"109","author":"Lemoine","year":"2022","journal-title":"Am. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ajhg.2021.11.016","article-title":"Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype","volume":"109","author":"Senum","year":"2022","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1111\/liv.15493","article-title":"A SEC61A1 variant is associated with autosomal dominant polycystic liver disease","volume":"43","author":"Schlevogt","year":"2023","journal-title":"Liver Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1093\/ndt\/gfy261","article-title":"Evolving role of genetic testing for the clinical management of autosomal dominant polycystic kidney disease","volume":"34","author":"Lanktree","year":"2018","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1007\/s10157-019-01736-3","article-title":"Mutation analyses by next-generation sequencing and multiplex ligation-dependent probe amplification in Japanese autosomal dominant polycystic kidney disease patients","volume":"23","author":"Mochizuki","year":"2019","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1038\/s41431-020-00796-4","article-title":"Genomic diagnostics in polycystic kidney disease: An assessment of real-world use of whole-genome sequencing","volume":"29","author":"Mallawaarachchi","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1016\/j.bbamcr.2013.04.001","article-title":"N-linked protein glycosylation in the ER","volume":"1833","author":"Aebi","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13023-015-0289-7","article-title":"ALG8-CDG: Novel patients and review of the literature","volume":"10","author":"Wegleiter","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1002\/jimd.12527","article-title":"ALG8-CDG: Molecular and phenotypic expansion suggests clinical management guidelines","volume":"45","author":"Albokhari","year":"2022","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1172\/JCI90129","article-title":"Isolated polycystic liver disease genes define effectors of polycystin-1 function","volume":"127","author":"Besse","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1681\/ASN.2018050493","article-title":"Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing","volume":"29","author":"Lanktree","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.kint.2022.11.025","article-title":"Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease","volume":"103","author":"Apple","year":"2022","journal-title":"Kidney Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2215\/CJN.05900519","article-title":"Epidemiology of Autosomal Dominant Polycystic Kidney Disease in Olmsted County","volume":"15","author":"Suwabe","year":"2020","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"100166","DOI":"10.1016\/j.jhepr.2020.100166","article-title":"Epidemiology of autosomal-dominant polycystic liver disease in Olmsted county","volume":"2","author":"Suwabe","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1681\/ASN.2019030298","article-title":"ALG9 Mutation Carriers Develop Kidney and Liver Cysts","volume":"30","author":"Besse","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1038\/s41436-020-0816-3","article-title":"Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes","volume":"22","author":"Baatz","year":"2020","journal-title":"Genet. Med."},{"key":"ref_43","first-page":"832","article-title":"Heterozygosity of ALG9 in association with autosomal dominant polycystic liver disease","volume":"102","author":"Boerrigter","year":"2023","journal-title":"Am. J. Hum. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.ajhg.2018.03.013","article-title":"Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease","volume":"102","author":"Olson","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1093\/ckj\/sfac032","article-title":"More dissimilarities than affinities between DNAJB11-PKD and ADPKD","volume":"15","author":"Pisani","year":"2022","journal-title":"Clin. Kidney J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.kint.2020.02.022","article-title":"Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease","volume":"98","author":"Huynh","year":"2020","journal-title":"Kidney Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1186\/s13023-020-01585-4","article-title":"Novel GANAB variants associated with polycystic liver disease","volume":"15","author":"Hoischen","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1016\/j.ajhg.2016.05.004","article-title":"Mutations in GANAB, Encoding the Glucosidase II\u03b1 Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease","volume":"98","author":"Porath","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s40620-021-01131-w","article-title":"Expanding the variability of the ADPKD-GANAB clinical phenotype in a family of Italian ancestry","volume":"35","author":"Delbarba","year":"2022","journal-title":"J. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1002\/humu.23383","article-title":"A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family","volume":"39","author":"Besse","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.ekir.2020.01.009","article-title":"Large Deletions in GANAB and SEC63 Explain 2 Cases of Polycystic Kidney and Liver Disease","volume":"5","author":"Wilson","year":"2020","journal-title":"Kidney Int. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5343","DOI":"10.1073\/pnas.1309438111","article-title":"Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis","volume":"111","author":"Cnossen","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/ejhg.2015.86","article-title":"LRP5 variants may contribute to ADPKD","volume":"24","author":"Cnossen","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"120","DOI":"10.21037\/atm-20-3318","article-title":"Association of a novel PKHD1 mutation in a family with autosomal dominant polycystic liver disease","volume":"9","author":"Wang","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"D20","DOI":"10.1093\/nar\/gkab1112","article-title":"Database resources of the national center for biotechnology information","volume":"50","author":"Sayers","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_56","unstructured":"The UniProt Consortium (2022). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res., 51, D523\u2013D531."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1177\/2050640615618042","article-title":"Creating an effective clinical registry for rare diseases","volume":"4","author":"Kievit","year":"2016","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/S0140-6736(94)92026-5","article-title":"Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1","volume":"343","author":"Ravine","year":"1994","journal-title":"Lancet"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1681\/ASN.2008050507","article-title":"Unified criteria for ultrasonographic diagnosis of ADPKD","volume":"20","author":"Pei","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e115","DOI":"10.1093\/nar\/gks596","article-title":"Primer3\u2014New capabilities and interfaces","volume":"40","author":"Untergasser","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_65","unstructured":"(2022, June 01). Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA. Available online: http:\/\/evs.gs.washington.edu\/EVS\/)."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"Varadi","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1093\/bioinformatics\/btu426","article-title":"YASARA View\u2014Molecular graphics for all devices\u2014From smartphones to workstations","volume":"30","author":"Krieger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Albuquerque-Wendt, A., H\u00fctte, H.J., Buettner, F.F.R., Routier, F.H., and Bakker, H. (2019). Membrane Topological Model of Glycosyltransferases of the GT-C Superfamily. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194842"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1111\/liv.15177","article-title":"Abdominal wall hernia is a frequent complication of polycystic liver disease and associated with hepatomegaly","volume":"42","author":"Barten","year":"2022","journal-title":"Liver Int."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"464","DOI":"10.3389\/fgene.2020.00464","article-title":"Gene Panel Analysis in a Large Cohort of Patients with Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families","volume":"11","author":"Mantovani","year":"2020","journal-title":"Front. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S1097-2765(00)80135-5","article-title":"Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease","volume":"2","author":"Watnick","year":"1998","journal-title":"Mol. Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1681\/ASN.V1071524","article-title":"Somatic PKD2 mutations in individual kidney and liver cysts support a \u201ctwo-hit\u201d model of cystogenesis in type 2 autosomal dominant polycystic kidney disease","volume":"10","author":"Pei","year":"1999","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1681\/ASN.2017050483","article-title":"Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases","volume":"29","author":"Torres","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1399-0004.1986.tb00565.x","article-title":"Adult polycystic liver and kidney diseases are separate entities","volume":"30","author":"Karhunen","year":"1986","journal-title":"Clin. Genet."},{"key":"ref_76","first-page":"1282","article-title":"Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease","volume":"26","author":"Sherstha","year":"1997","journal-title":"Hepatology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1002\/ajmg.a.62065","article-title":"SRD5A3-CDG: 3D structure modeling, clinical spectrum, and computer-based dysmorphic facial recognition","volume":"185","author":"Ouarda","year":"2021","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ceb.2016.03.021","article-title":"N-linked glycosylation and homeostasis of the endoplasmic reticulum","volume":"41","author":"Cherepanova","year":"2016","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13023-020-01630-2","article-title":"Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: Pin-pointing the characteristics of liver injury and proposing recommendations for follow-up","volume":"16","author":"Starosta","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s00439-017-1809-4","article-title":"Deep intronic mutations and human disease","volume":"136","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.ymgme.2007.01.003","article-title":"Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients","volume":"90","author":"Schollen","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1002\/humu.20960","article-title":"Functional analysis of three splicing mutations identified in the PMM2 gene: Toward a new therapy for congenital disorder of glycosylation type Ia","volume":"30","author":"Vega","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1111\/j.1399-0004.2008.01106.x","article-title":"Pseudoexon activation in the PKHD1 gene: A French founder intronic mutation IVS46+653A>G causing severe autosomal recessive polycystic kidney disease","volume":"75","author":"Dijoud","year":"2009","journal-title":"Clin. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s10038-018-0550-8","article-title":"A rare deep intronic mutation of PKHD1 gene, c.8798-459\u2009C\u2009>\u2009A, causes autosomal recessive polycystic kidney disease by pseudoexon activation","volume":"64","author":"Chen","year":"2019","journal-title":"J. Hum. 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