Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

被引：71

作者：

Berauer, John-Paul ^{[1
,2
]}

Mezina, Anya I. ^{[1
,2
]}

Okou, David T. ^{[1
,2
]}

Sabo, Aniko ^{[3
]}

Muzny, Donna M. ^{[3
]}

Gibbs, Richard A. ^{[3
]}

Hegde, Madhuri R. ^{[4
]}

Chopra, Pankaj ^{[4
]}

Cutler, David J. ^{[4
]}

Perlmutter, David H. ^{[5
]}

Bull, Laura N. ^{[6
,7
]}

Thompson, Richard J. ^{[8
]}

Loomes, Kathleen M. ^{[9
,10
]}

Spinner, Nancy B. ^{[11
]}

Rajagopalan, Ramakrishnan ^{[11
,12
]}

Guthery, Stephen L. ^{[13
,14
]}

Moore, Barry ^{[15
]}

Yandell, Mark ^{[15
]}

Harpavat, Sanjiv ^{[16
]}

Magee, John C. ^{[17
]}

Kamath, Binita M. ^{[18
,19
]}

Molleston, Jean P. ^{[20
,21
]}

Bezerra, Jorge A. ^{[22
]}

Murray, Karen F. ^{[23
]}

Alonso, Estella M. ^{[24
]}

Rosenthal, Philip ^{[25
]}

Squires, Robert H. ^{[26
]}

Wang, Kasper S. ^{[27
]}

Finegold, Milton J. ^{[28
]}

Russo, Pierre ^{[29
]}

Sherker, Averell H. ^{[30
]}

Sokol, Ronald J. ^{[31
,32
]}

Karpen, Saul J. ^{[1
,2
]}

机构：

[1] Emory Univ, Sch Med, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Atlanta, GA USA

[2] Childrens Healthcare Atlanta, Atlanta, GA USA

[3] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[4] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA

[5] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA

[6] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA

[7] Univ Calif San Francisco, Dept Med, Liver Ctr Lab, San Francisco, CA 94143 USA

[8] Kings Coll London, Inst Liver Studies, London, England

[9] Univ Penn, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Perelman Sch Med, Philadelphia, PA 19104 USA

[10] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[11] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Div Genom Diagnost, Philadelphia, PA 19104 USA

[12] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA

[13] Univ Utah, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Salt Lake City, UT USA

[14] Intermt Primary Childrens Hosp, Salt Lake City, UT USA

[15] Univ Utah, Dept Human Genet, Salt Lake City, UT USA

[16] Baylor Coll Med, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA

[17] Univ Michigan, Sch Med, Ann Arbor, MI USA

[18] Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON, Canada

[19] Univ Toronto, Toronto, ON, Canada

[20] Indiana Univ Sch Med, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Indianapolis, IN 46202 USA

[21] Riley Hosp Children, Indianapolis, IN USA

[22] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA

[23] Univ Washington, Sch Med, Dept Pediat, Div Gastroenterol & Hepatol, Seattle, WA 98195 USA

[24] Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Chicago, IL 60611 USA

[25] Univ Calif San Francisco, Dept Pediat, Div Gastroenterol Hepatol & Nutr, San Francisco, CA USA

[26] UPMC, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Childrens Hosp Pittsburgh, Pittsburgh, PA USA

[27] Univ Southern Calif, Dept Surg, Div Pediat Surg, Childrens Hosp Los Angeles, Los Angeles, CA USA

[28] Baylor Coll Med, Dept Pediat, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[29] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[30] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA

[31] Childrens Hosp Colorado, Dept Pediat, Sect Gastroenterol Hepatol & Nutr, Aurora, CO USA

[32] Univ Colorado, Sch Med, Aurora, CO USA

来源：

HEPATOLOGY | 2019年 / 70卷 / 03期

基金：

美国国家卫生研究院;

关键词：

PRIMARY CILIA; CHOLANGIOCYTE CILIA; PATHOGENESIS; HEALTH; INVOLVEMENT; PKD1L1;

D O I：

10.1002/hep.30515

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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 National Institute of Diabetes and Digestive and Kidney Diseases-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified 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 biallelic variants in polycystic kidney disease 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 noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.

引用

页码：899 / 910

页数：12

共 50 条

[1]

Ensembl 2017 [J].

Aken, Bronwen L. ;

Achuthan, Premanand ;

Akanni, Wasiu ;

Amode, M. Ridwan ;

Bernsdorff, Friederike ;

Bhai, Jyothish ;

Billis, Konstantinos ;

Carvalho-Silva, Denise ;

Cummins, Carla ;

Clapham, Peter ;

Gil, Laurent ;

Giron, Carlos Garcia ;

Gordon, Leo ;

Hourlier, Thibaut ;

Hunt, Sarah E. ;

Janacek, Sophie H. ;

Juettemann, Thomas ;

Keenan, Stephen ;

Laird, Matthew R. ;

Lavidas, Ilias ;

Maurel, Thomas ;

McLaren, William ;

Moore, Benjamin ;

Murphy, Daniel N. ;

Nag, Rishi ;

Newman, Victoria ;

Nuhn, Michael ;

Ong, Chuang Kee ;

Parker, Anne ;

Patricio, Mateus ;

Riat, Harpreet Singh ;

Sheppard, Daniel ;

Sparrow, Helen ;

Taylor, Kieron ;

Thormann, Anja ;

Vullo, Alessandro ;

Walts, Brandon ;

Wilder, Steven P. ;

Zadissa, Amonida ;

Kostadima, Myrto ;

Martin, Fergal J. ;

Muffato, Matthieu ;

Perry, Emily ;

Ruffier, Magali ;

Staines, Daniel M. ;

Trevanion, Stephen J. ;

Cunningham, Fiona ;

Yates, Andrew ;

Zerbino, Daniel R. ;

Flicek, Paul .

NUCLEIC ACIDS RESEARCH, 2017, 45 (D1) :D635-D642

[2]

Arnaiz Olivier, 2014, Cilia, V3, P9, DOI 10.1186/2046-2530-3-9

[3]

Cildb: a knowledgebase for centrosomes and cilia [J].

Arnaiz, Olivier ;

Malinowska, Agata ;

Klotz, Catherine ;

Sperling, Linda ;

Dadlez, Michal ;

Koll, France ;

Cohen, Jean .

DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION, 2009,

[4]

Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes [J].

Asai, Akihiro ;

Miethke, Alexander ;

Bezerra, Jorge A. .

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, 2015, 12 (06) :342-352

[5]

Biliary Atresia: Clinical and Research Challenges for the Twenty-First Century [J].

Bezerra, Jorge A. ;

Wells, Rebecca G. ;

Mack, Cara L. ;

Karpen, Saul J. ;

Hoofnagle, Jay H. ;

Doo, Edward ;

Sokol, Ronald J. .

HEPATOLOGY, 2018, 68 (03) :1163-1173

[6]

Ciliopathies [J].

Braun, Daniela A. ;

Hildebrandt, Friedhelm .

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2017, 9 (03)

[7]

Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia [J].

Chu, Andrew S. ;

Russo, Pierre A. ;

Wells, Rebecca G. .

MODERN PATHOLOGY, 2012, 25 (05) :751-757

[8]

Evidence From Human and Zebrafish That GPC1 Is a Biliary Atresia Susceptibility Gene [J].

Cui, Shuang ;

Leyva-Vega, Melissa ;

Tsai, Ellen A. ;

Eauclaire, Steven F. ;

Glessner, Joseph T. ;

Hakonarson, Hakon ;

Devoto, Marcella ;

Haber, Barbara A. ;

Spinner, Nancy B. ;

Matthews, Randolph P. .

GASTROENTEROLOGY, 2013, 144 (05) :1107-+

[9]

DAVENPORT M, 1993, SURGERY, V113, P662

[10]

The biliary atresia splenic malformation syndrome: A 28-year single-center retrospective study [J].

Davenport, Mark ;

Tizzard, Sarah A. ;

Underhill, James ;

Mieli-Vergani, Giorgina ;

Portmann, Bernard ;

Hadzic, Nedim .

JOURNAL OF PEDIATRICS, 2006, 149 (03) :393-400

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