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Browsing by Author "Bull, Laura N."
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Item Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome(Wiley, 2019) Berauer, John-Paul; Mezina, Anya I.; Okou, David T.; Sabo, Aniko; Muzny, Donna M.; Gibbs, Richard A.; Hegde, Madhuri R.; Chopra, Pankaj; Cutler, David J.; Perlmutter, David H.; Bull, Laura N.; Thompson, Richard J.; Loomes, Kathleen M.; Spinner, Nancy B.; Rajagopalan, Ramakrishnan; Guthery, Stephen L.; Moore, Barry; Yandell, Mark; Harpavat, Sanjiv; Magee, John C.; Kamath, Binita M.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Alonso, Estella M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper S.; Finegold, Milton J.; Russo, Pierre; Sherker, Averell H.; Sokol, Ronald J.; Karpen, Saul J.; Pediatrics, School of MedicineBiliary 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 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.Item Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome(Wiley, 2019-01-21) Berauer, John-Paul; Mezina, Anya I.; Okou, David T.; Sabo, Aniko; Muzny, Donna M.; Gibbs, Richard A.; Hegde, Madhuri R.; Chopra, Pankaj; Cutler, David J.; Perlmutter, David H.; Bull, Laura N.; Thompson, Richard J.; Loomes, Kathleen M.; Spinner, Nancy B.; Rajagopalan, Ramakrishnan; Guthery, Stephen L.; Moore, Barry; Yandell, Mark; Harpavat, Sanjiv; Magee, John C.; Kamath, Binita M.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Alonso, Estella M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper S.; Finegold, Milton J.; Russo, Pierre; Sherker, Averell H.; Sokol, Ronald J.; Karpen, Saul J.; Pediatrics, School of MedicineBiliary 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 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.Item Presentation and Outcomes of Infants With Idiopathic Cholestasis: A Multicenter Prospective Study(Wolters Kluwer, 2021-10-01) Hertel, Paula M.; Hawthorne, Kieran; Kim, Sehee; Finegold, Milton J.; Shneider, Benjamin L.; Squires, James E.; Gupta, Nitika A.; Bull, Laura N.; Murray, Karen F.; Kerkar, Nanda; Ng, Vicky L.; Molleston, Jean P.; Bezerra, Jorge A.; Loomes, Kathleen M.; Taylor, Sarah A.; Schwarz, Kathleen B.; Turmelle, Yumirle P.; Rosenthal, Philip; Magee, John C.; Sokol, Ronald J.; Pediatrics, School of MedicineObjectives: The aim of the study was to determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multicenter cohort of infants. Methods: We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they were followed up to 30 months of age. Results: Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at < 37 weeks' gestational age), and low birth weight (25/89; 28% born at <2500 g) were frequent, with no significant differences between outcomes. Clinical outcomes included death (n = 1), liver transplant (n = 1), biochemical resolution (total bilirubin [TB] ≤1 mg/dL and ALT < 35 U/L; n = 51), partial resolution (TB > 1 mg/dL and/or ALT > 35 U/L; n = 7), and exited healthy (resolved disease per study site report but without documented biochemical resolution; n = 34). Biochemical resolution occurred at median of 9 months of age. GGT was <100 U/L at baseline in 34 of 83 participants (41%). Conclusions: Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely because of recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis-this warrants further study.