https://www.ncbi.nlm.nih.gov/pubmed/30664273 Biliary atresia

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.

Berauer JP1, Mezina AI1, Okou DT1, Sabo A2, Muzny DM2, Gibbs RA2, Hegde MR3, Chopra P3, Cutler DJ3, Perlmutter DH4, Bull LN5, Thompson RJ6, Loomes KM7, Spinner NB8, Rajagopalan R8,9, Guthery SL10, Moore B11, Yandell M11, Harpavat S12, Magee JC13, Kamath BM14, Molleston JP15, Bezerra JA16, Murray KF17, Alonso EM18, Rosenthal P19, Squires RH20, Wang KS21, Finegold MJ22, Russo P23, Sherker AH24, Sokol RJ25, Karpen SJ1; Childhood Liver Disease Research Network (ChiLDReN).

Abstract

Biliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric livertransplantation, 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.