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Hepatology. 2019 Jan 21. doi: 10.1002/hep.30515. [Epub ahead of print]

Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome.

Author information

1
Department of Pediatrics; Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, 30322, USA.
2
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
3
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
4
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
5
Institute for Human Genetics, and Liver Center Laboratory, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
6
Institute of Liver Studies, King's College London, London, SE5 9RS, UK.
7
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Perelman School of Medicine at the University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
8
Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
9
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
10
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Utah; and Intermountain Primary Children's Hospital Salt Lake City, UT, 84112, USA.
11
Department of Human Genetics, University of Utah, Salt Lake City, UT, 84112, USA.
12
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Houston, TX, 77030, USA.
13
University of Michigan Medical School, Ann Arbor, MI, 48103, USA.
14
Division of Gastroenterology, Hepatology and Nutrition; Hospital for Sick Children and University of Toronto, Toronto, ON, M5G 1X8, Canada.
15
Department of Pediatrics; Division of Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine and Riley Hospital for Children; Indianapolis, IN, 46202, USA.
16
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
17
Department of Pediatrics, Division of Gastroenterology and Hepatology, University of Washington, School of Medicine and Seattle Children's Hospital, Seattle, WA, 98105, USA.
18
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA.
19
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of California San Francisco, San Francisco, CA, 94143, USA.
20
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
21
Department of Surgery, Division of Pediatric Surgery, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CO, 90027, USA.
22
Department of Pediatrics, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
23
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
24
Liver Diseases Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
25
Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Abstract

Biliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations - a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the NIDDK-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre-specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi-allelic variants in polycystin 1-like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non-cholestatic diseases. Conclusion WES identified bi-allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome. This article is protected by copyright. All rights reserved.

KEYWORDS:

Cholangiocyte; Cilia; Laterality; Neonatal Cholestasis; Whole Exome Sequencing

PMID:
30664273
DOI:
10.1002/hep.30515

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