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

TitleIdentification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome.
Publication TypeJournal Article
Year of Publication2019
AuthorsBerauer, J-P, Mezina, AI, Okou, DT, Sabo, A, Muzny, DM, Gibbs, RA, Hegde, MR, Chopra, P, Cutler, DJ, Perlmutter, DH, Bull, LN, Thompson, RJ, Loomes, KM, Spinner, NB, Rajagopalan, R, Guthery, SL, Moore, B, Yandell, M, Harpavat, S, Magee, JC, Kamath, BM, Molleston, JP, Bezerra, JA, Murray, KF, Alonso, EM, Rosenthal, P, Squires, RH, Wang, KS, Finegold, MJ, Russo, P, Sherker, AH, Sokol, RJ, Karpen, SJ
Corporate AuthorsChildhood Liver Disease Research Network (ChiLDReN)
JournalHepatology
Date Published2019 Jan 21
ISSN1527-3350
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.

DOI10.1002/hep.30515
Alternate JournalHepatology
PubMed ID30664273
Grant List / / Meredith Brown Foundation /
U54 HG003273 / / American Gastroenterological Association /
TL1TR000456 / / American Gastroenterological Association /
/ / The Cade R. Alpard Foundation for Pediatric Liver Disease /
/ / The Spain Foundation /
DK103149 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK103140 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK103135 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK084575 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK084538 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK084536 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062503 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062500 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062497 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062481 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062470 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062466 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062456 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062453 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062452 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062445 / / National Institute of Diabetes and Digestive and Kidney Diseases /
DK062436 / / National Institute of Diabetes and Digestive and Kidney Diseases /
TR001872 / / National Center for Advancing Translational Sciences /
TR001857 / / National Center for Advancing Translational Sciences /
TR001108 / / National Center for Advancing Translational Sciences /
TR002535 / / National Center for Advancing Translational Sciences /
TR002378 / / National Center for Advancing Translational Sciences /
TR000423 / / National Center for Advancing Translational Sciences /
RR025014 / / National Center for Advancing Translational Sciences /
TR000077 / / National Center for Advancing Translational Sciences /
TR000003 / / National Center for Advancing Translational Sciences /
U01 DK062481 / DK / NIDDK NIH HHS / United States
U01 DK062470 / DK / NIDDK NIH HHS / United States
UL1 TR001857 / TR / NCATS NIH HHS / United States
U01 DK103140 / DK / NIDDK NIH HHS / United States
UL1 TR001872 / TR / NCATS NIH HHS / United States
U01 DK084538 / DK / NIDDK NIH HHS / United States
U01 DK062453 / DK / NIDDK NIH HHS / United States
U01 DK062503 / DK / NIDDK NIH HHS / United States
UL1 TR002535 / TR / NCATS NIH HHS / United States
U01 DK103135 / DK / NIDDK NIH HHS / United States
U01 DK062436 / DK / NIDDK NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U01 DK062452 / DK / NIDDK NIH HHS / United States
U01 DK062466 / DK / NIDDK NIH HHS / United States
UL1 TR000003 / TR / NCATS NIH HHS / United States
TL1 TR000456 / TR / NCATS NIH HHS / United States
U01 DK084575 / DK / NIDDK NIH HHS / United States
UL1 RR025014 / RR / NCRR NIH HHS / United States
UL1 TR002378 / TR / NCATS NIH HHS / United States
U01 DK084536 / DK / NIDDK NIH HHS / United States
U01 DK062456 / DK / NIDDK NIH HHS / United States
UL1 TR000077 / TR / NCATS NIH HHS / United States
UL1 TR000423 / TR / NCATS NIH HHS / United States
U01 DK103149 / DK / NIDDK NIH HHS / United States
U01 DK062497 / DK / NIDDK NIH HHS / United States