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

the Childhood Liver Disease Research Network (ChiLDReN)

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 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.

Original languageEnglish (US)
JournalHepatology
DOIs
StatePublished - Jan 1 2019

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Biliary Atresia
Polycystic Kidney Diseases
Genes
Exome
Liver Diseases
Liver
End Stage Liver Disease
Calcium Signaling
Cholestasis
Bile Ducts
Research
Liver Transplantation
Virulence
Fishes
Epithelium
Pediatrics
Kidney

ASJC Scopus subject areas

  • Hepatology

Cite this

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome. / the Childhood Liver Disease Research Network (ChiLDReN).

In: Hepatology, 01.01.2019.

Research output: Contribution to journalArticle

@article{3019295085434b4fbba93341da0c11a6,
title = "Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome",
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 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.",
author = "{the Childhood Liver Disease Research Network (ChiLDReN)} and Berauer, {John Paul} and Mezina, {Anya I.} and Okou, {David T.} and Aniko Sabo and Muzny, {Donna M.} and Gibbs, {Richard A.} and Hegde, {Madhuri R.} and Pankaj Chopra and Cutler, {David J.} and Perlmutter, {David H.} and Bull, {Laura N.} and Thompson, {Richard J.} and Loomes, {Kathleen M.} and Spinner, {Nancy B.} and Ramakrishnan Rajagopalan and Guthery, {Stephen L.} and Barry Moore and Mark Yandell and Sanjiv Harpavat and Magee, {John C.} and Kamath, {Binita M.} and Jean Molleston and Bezerra, {Jorge A.} and Murray, {Karen F.} and Alonso, {Estella M.} and Philip Rosenthal and Squires, {Robert H.} and Wang, {Kasper S.} and Finegold, {Milton J.} and Pierre Russo and Sherker, {Averell H.} and Sokol, {Ronald J.} and Karpen, {Saul J.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1002/hep.30515",
language = "English (US)",
journal = "Hepatology",
issn = "0270-9139",
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T1 - Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

AU - the Childhood Liver Disease Research Network (ChiLDReN)

AU - Berauer, John Paul

AU - Mezina, Anya I.

AU - Okou, David T.

AU - Sabo, Aniko

AU - Muzny, Donna M.

AU - Gibbs, Richard A.

AU - Hegde, Madhuri R.

AU - Chopra, Pankaj

AU - Cutler, David J.

AU - Perlmutter, David H.

AU - Bull, Laura N.

AU - Thompson, Richard J.

AU - Loomes, Kathleen M.

AU - Spinner, Nancy B.

AU - Rajagopalan, Ramakrishnan

AU - Guthery, Stephen L.

AU - Moore, Barry

AU - Yandell, Mark

AU - Harpavat, Sanjiv

AU - Magee, John C.

AU - Kamath, Binita M.

AU - Molleston, Jean

AU - Bezerra, Jorge A.

AU - Murray, Karen F.

AU - Alonso, Estella M.

AU - Rosenthal, Philip

AU - Squires, Robert H.

AU - Wang, Kasper S.

AU - Finegold, Milton J.

AU - Russo, Pierre

AU - Sherker, Averell H.

AU - Sokol, Ronald J.

AU - Karpen, Saul J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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U2 - 10.1002/hep.30515

DO - 10.1002/hep.30515

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