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1034A AASLD ABSTRACTS HEPATOLOGY, October, 2015 Th1 cytokines (TNF-α and IFN-γ) and innate cytokines (IL-1, IL-6) in WT-RRV mice but not BSS controls or Ig-α -/- RRV groups. Conclusions: The RRV-induced mouse model of BA is associated with an abnormal decrease in the expression of the majority of transporters involved in bile excretion. The high levels of retained bile acids may contribute to liver injury. The lack of inflammation within the Ig-α -/- RRV mice is associated with normal expression of the majority of bile acid transporter proteins, suggesting that the inflammation present in RRV-induced BA mice inappropriately inhibits bile acid transporter expression. Disclosures: The following authors have nothing to disclose: Asokan Rengasamy, Karim C. El Kasmi, Brianna Traxinger, Jonathan Roach, Natarajan Balasubramaniyan, Cara L. Mack 1693 Exome Sequencing and de novo Mutation Analysis Reveal a Highly Connected Gene Network in Isolated Biliary Atresia Kathleen M. Loomes 5,1 , Ramakrishnan Rajagopalan 2 , Christopher Grochowski 2 , Ying Chen 3,4 , Melissa Gilbert 2 , Henry C. Lin 5,1 , Marcella Devoto 4,1 , Nancy B. Spinner 2,6 ; 1 Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 2 Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA; 3 Genomics and Computational Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 4 Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA; 5 Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA; 6 Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA Biliary atresia (BA) is a severe pediatric liver disease resulting in necroinflammatory obliteration of the extrahepatic biliary tree. The majority of BA patients develop biliary cirrhosis and 50% will require liver transplantation in the first two years of life. Incidence of BA is reported to be between 1 in 18,000 and 1 in 8,000 depending on ethnicity. The etiology of BA is unknown, with evidence for infectious, environmental, and genetic risk factors described. The purpose of this study was to investigate possible genetic etiologies of BA by whole exome sequencing of non-syndromic BA probands and their parents (trios). DNA samples were obtained from 10 well-characterized non-syndromic BA probands and their parents from the NIDDK-funded Childhood Liver Disease Research Network (ChiLDReN). We performed whole-exome sequencing in these 10 trios and looked for de novo mutations under the assumption that mutations only seen in probands, but not the parents, are more likely to be involved in the etiology of the disease. We used a custom in-house computational analysis pipeline to call variants and identify de novo mutations. We found a total of 33 exonic de novo variants in 33 different genes. These were 2 loss-of-function mutations, 3 in-frame insertions/deletions, 2 splice-site mutations and 26 missense mutations. The number of de novo changes per proband ranged from 1 to 9 with a mean of 3.3. Seven of the 10 probands carried more than 1 de novo mutation. However, none of the mutations was seen in more than one proband. We used protein-interaction network analysis tools such as GeneMANIA, DAPPLE and Ingenuity Pathway Analysis (IPA) to assess 1) whether the genes with de novo mutations are connected with each other directly or through a single common partner, 2) whether the genes with de novo mutations form a network with genes previously implicated in BA. Gene network analysis with GeneMANIA suggested a highly interconnected network of proteins that are co-expressed. Protein interaction analysis with DAPPLE suggested that 17 out of 33 genes (51%) interact with each other directly or through a single common partner to form a tight network. We used IPA to explore the paths between the genes with de novo mutations and genes previously implicated in BA. Network connectivity analyses with IPA suggest that 29 out of 33 genes (88%) are at most 2 nodes away from a group of 19 selected BA candidate genes. Results from network analysis suggest a shared etiology to seemingly sporadic de novo mutations observed in probands with isolated BA. To our knowledge, this is the first report of trio analysis for isolated BA using next-generation sequencing technology. Disclosures: The following authors have nothing to disclose: Kathleen M. Loomes, Ramakrishnan Rajagopalan, Christopher Grochowski, Ying Chen, Melissa Gilbert, Henry C. Lin, Marcella Devoto, Nancy B. Spinner 1694 DXA Bone Density in Alagille Syndrome Correlates with Fracture History and Degree of Cholestasis Kathleen M. Loomes 2 , Cathie Spino 14 , Nathan P. Goodrich 1 , Thomas N. Hangartner 15 , Amanda E. Marker 15 , James E. Heubi 16 , Binita M. Kamath 13 , Benjamin Shneider 17 , Philip Rosenthal 3 , Paula M. Hertel 17 , Saul J. Karpen 4 , Nanda Kerkar 5,19 , Jean P. Molleston 6 , Karen F. Murray 7 , Kathleen B. Schwarz 8 , Jeffrey Teckman 18 , Yumirle P. Turmelle 9 , Peter F. Whitington 20 , Averell H. Sherker 10 , John C. Magee 11 , Ronald J. Sokol 12 ; 1 Arbor Research Collaborative for Health, Ann Arbor, MI; 2 Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA; 3 Division of GI, Hepatology and Nutrition, UCSF-University of California, San Francisco, San Francisco, CA; 4 Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine/Children’s Healthcare of Atlanta, Atlanta, GA; 5 Children’s Hospital of Los Angeles, Los Angeles, CA; 6 Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, IN; 7 Division of Gastroenterology and Hepatology, University of Washington Medical Center, Seattle Children’s, Seattle, WA; 8 Johns Hopkins School of Medicine, Baltimore, MD; 9 Washington University School of Medicine, Saint Louis, MO; 10 Liver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; 11 University of Michigan Medical School, Ann Arbor, MI; 12 Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado, Aurora, CO; 13 Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada; 14 University of Michigan, Ann Arbor, MI; 15 Department of Biomedical, Industrial, & Human Factors Engineering, Wright State University, Dayton, OH; 16 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; 17 Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Houston, TX; 18 Saint Louis University, Cardinal Glennon Children’s Medical Center, St. Louis, MO; 19 Mount Sinai, New York, NY; 20 Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg Medical School, Chicago, IL Osteopenia and bone fractures (fx) are significant causes of morbidity in children with cholestatic liver disease. We performed dual energy X-ray absorptiometry (DXA) analysis in a cohort of children with inherited cholestatic diseases and explored associations with anthropometrics, laboratory measurements and fx history. Methods: Subjects were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC) in the NIDDK-funded Childhood Liver
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1035A Disease Research Network (ChiLDReN). DXA was performed on subjects age > 5 years (with native liver), diagnosed with Bile Acid Synthetic Disorder (BAD; n=14), Alpha-1 antitrypsin deficiency (A1AT; n=44) and Alagille syndrome (ALGS; n=49). Pearson correlation coefficients examined associations between subject reference (adjusted for age, gender and race) and anthropometrically-adjusted DXA Z-scores and laboratory values (total bilirubin (TB), serum bile acids (SBA) and 25-OH vitamin D (vitD)) and fx history. Results: Weight, height and BMI Z-scores were all lower, and TB and SBA higher, in the ALGS group (p1 fx; 21% and 7% in BAD; 20% and 2% in A1AT). Bone mineral density (BMD) reference measures did not differ among disease groups except for total hip BMD and femoral neck BMD, which were lower in ALGS (p=0.007 and p=0.0002). Total body and total body minus head bone mineral content (BMC) reference measures were lower in the ALGS subjects (p
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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1366A CATEGORY INDEX HEPATOLOGY, Oc
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