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Eur J Hum Genet. 2016 Dec;24(12):1707-1714. doi: 10.1038/ejhg.2016.97. Epub 2016 Aug 24.

Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes.

Author information

1
Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
2
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
3
Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
4
Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Wellcome Trust/Cancer Research UK Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Cambridge, UK.
6
Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
7
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
8
Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

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.

PMID:
27552964
PMCID:
PMC5117941
DOI:
10.1038/ejhg.2016.97
[Indexed for MEDLINE]
Free PMC Article

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