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Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic
John-Paul Berauer1, Anya I Mezina1, David T Okou1
1Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA.
Insights
Genetic factors in biliary atresia splenic malformation (BASM) syndrome were investigated. Whole-exome sequencing identified PKD1L1 gene variants in affected infants, suggesting its role in this pediatric liver disease.
Area of Science:
- Genetics
- Pediatric Gastroenterology
- Developmental Biology
Background:
- Biliary atresia (BA) is a leading cause of pediatric liver disease and transplantation.
- The biliary atresia splenic malformation (BASM) syndrome, a subgroup of BA, presents with laterality defects and unknown genetic causes.
- Understanding BA etiology is crucial for improving diagnosis and treatment.
Purpose of the Study:
- To identify genetic factors contributing to the etiopathogenesis of biliary atresia splenic malformation (BASM) syndrome.
- To investigate the role of candidate genes involved in ciliary function and cholestasis in BASM patients.
- To explore the link between laterality defects and BA in the BASM subgroup.
Main Methods:
- Whole-exome sequencing (WES) was performed on 67 BASM subjects (58 trios) from the Childhood Liver Disease Research Network (ChiLDReN).
- Candidate gene variants were prioritized based on pathogenicity, population frequency, and inheritance patterns, focusing on genes related to ciliary dysfunction or cholestasis.
- Immunohistochemical analysis assessed PKD1L1 expression in liver tissue.
Main Results:
- Rare, potentially deleterious biallelic variants in PKD1L1 were identified in five BASM subjects.
- Heterozygous PKD1L1 variants were found in three additional subjects.
- Decreased PKD1L1 expression was observed in the bile duct epithelium of a BASM liver sample.
Conclusions:
- Whole-exome sequencing identified PKD1L1 variants in BASM subjects, implicating this gene in the syndrome.
- PKD1L1's known roles in laterality determination and ciliary function make it a strong candidate gene for BASM.
- Further research into PKD1L1's function is warranted to understand its contribution to pediatric liver disease.
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.
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