title: Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes.
abstract: Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Edgar S
authors.initials: ES
authors.lastname: Wills
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Wybrich R
authors.initials: WR
authors.lastname: Cnossen
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Woestenenk
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: Steehouwer
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jody
authors.initials: J
authors.lastname: Salomon
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: René H M
authors.initials: RH
authors.lastname: Te Morsche
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Cambridge, UK.|Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Huch
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Banning
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002135:Calcium-Binding Proteins; D002869:Chromosome Aberrations; D041321:Chromosomes, Human, X; D003560:Cysts / Q000235:genetics* / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D005959:Glucosidases / Q000235:genetics; D057895:Haploinsufficiency; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012729:Sex Chromosome Aberrations; D058533:Sex Chromosome Disorders of Sex Development; D050396:TRPP Cation Channels / Q000235:genetics; D014314:Trisomy
chemical_list: D002135:Calcium-Binding Proteins; D005959:Glucosidases; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D050396:TRPP Cation Channels; C584277:BUB1 protein, human; C070368:PRKCSH protein, human