Variants Associated with Infantile Cholestatic Syndromes Detected in Extrahepatic Biliary Atresia by Whole Exome Studies: A 20-Case Series from Thailand

Surasak Sangkhathat; Wison Laochareonsuk; Wanwisa Maneechay; Kanita Kayasut; Piyawan Chiengkriwate

doi:10.1055/s-0038-1632395

Journal of Pediatric Genetics, Table of Contents

J Pediatr Genet 2018; 07(02): 067-073
DOI: 10.1055/s-0038-1632395

Original Article

Georg Thieme Verlag KG Stuttgart · New York

Variants Associated with Infantile Cholestatic Syndromes Detected in Extrahepatic Biliary Atresia by Whole Exome Studies: A 20-Case Series from Thailand

Authors

Surasak Sangkhathat

¹Pediatric Surgery Unit, Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla, Thailand
Wison Laochareonsuk

¹Pediatric Surgery Unit, Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla, Thailand
Wanwisa Maneechay

²Central Research Laboratory, Prince of Songkla University, Hat Yai, Songkhla, Thailand
Kanita Kayasut

³Anatomical Pathology Unit, Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
Piyawan Chiengkriwate

¹Pediatric Surgery Unit, Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla, Thailand

Abstract

Biliary atresia (BA) is the most severe form of obstructive cholangiopathy occurring in infants. Definitive diagnosis of BA usually relies on operative findings together with supporting pathological patterns found in the extrahepatic bile duct. In infancy, overlapping clinical patterns of cholestasis can be found in other diseases including biliary hypoplasia and progressive familial intrahepatic cholestasis. In addition, BA has been reported as a phenotype in some rare genetic syndromes. Unlike BA, other cholangiopathic phenotypes have their own established genetic markers. In this study, we used these markers to look for other cholestasis entities in cases diagnosed with BA. DNA from 20 cases of BA, diagnosed by operative findings and histopathology, were subjected to a study of 19 genes associated with infantile cholestasis syndromes, using whole exome sequencing. Variant selection focused on those with allele frequencies in dbSNP150 of less than 0.01. All selected variants were verified by polymerase chain reaction–direct sequencing. Of the 20 cases studied, 13 rare variants were detected in 9 genes: 4 in JAG1 (Alagille syndrome), 2 in MYO5B (progressive familial intrahepatic cholestasis [PFIC] type 6), and one each in ABCC2 (Dubin–Johnson syndrome), ABCB11 (PFIC type 2), UG1A1 (Crigler–Najjar syndrome), MLL2 (Kabuki syndrome), RFX6 (Mitchell–Riley syndrome), ERCC4 (Fanconi anemia), and KCNH1 (Zimmermann–Laband syndrome). Genetic lesions associated with various cholestatic syndromes detected in cases diagnosed with BA raised the hypothesis that severe inflammatory cholangiopathy in BA may not be a distinct disease entity, but a shared pathology among several infantile cholestatic syndromes.

Keywords

biliary atresia - progressive familial intrahepatic cholestasis - JAG1

Full Text

References

References
1 Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009; 374 (9702): 1704-1713
2 Sangkhathat S, Patrapinyokul S, Tadtayathikom K, Osatakul S. Peri-operative factors predicting the outcome of hepatic porto-enterostomy in infants with biliary atresia. J Med Assoc Thai 2003; 86 (03) 224-231
3 Kang N, Davenport M, Driver M, Howard ER. Hepatic histology and the development of esophageal varices in biliary atresia. J Pediatr Surg 1993; 28 (01) 63-66
4 Cheng G, Tang CS, Wong EH. , et al. Common genetic variants regulating ADD3 gene expression alter biliary atresia risk. J Hepatol 2013; 59 (06) 1285-1291
5 Davenport M, Savage M, Mowat AP, Howard ER. Biliary atresia splenic malformation syndrome: an etiologic and prognostic subgroup. Surgery 1993; 113 (06) 662-668
6 Sanchez-Valle A, Kassira N, Varela VC, Radu SC, Paidas C, Kirby RS. Biliary atresia: epidemiology, genetics, clinical update, and public health perspective. Adv Pediatr 2017; 64 (01) 285-305
7 Mitchell J, Punthakee Z, Lo B. , et al. Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome. Diabetologia 2004; 47 (12) 2160-2167
8 Bogliolo M, Schuster B, Stoepker C. , et al. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet 2013; 92 (05) 800-806
9 Balasubramanian M, Parker MJ. Zimmermann-Laband syndrome in a child previously described with brachydactyly, extrahepatic biliary atresia, patent ductus arteriosus and seizures. Clin Dysmorphol 2010; 19 (01) 48-50
10 Raymond WR, Kearney JJ, Parmley VC. Ocular findings in arteriohepatic dysplasia (Alagille's syndrome). Arch Ophthalmol 1989; 107 (07) 1077
11 McDaniell R, Warthen DM, Sanchez-Lara PA. , et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 2006; 79 (01) 169-173
12 McGaughran JM, Donnai D, Clayton-Smith J. Biliary atresia in Kabuki syndrome. Am J Med Genet 2000; 91 (02) 157-158
13 van Haelst MM, Brooks AS, Hoogeboom J. , et al. Unexpected life-threatening complications in Kabuki syndrome. Am J Med Genet 2000; 94 (02) 170-173
14 de Vree JM, Jacquemin E, Sturm E. , et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A 1998; 95 (01) 282-287
15 Klomp LW, Vargas JC, van Mil SW. , et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004; 40 (01) 27-38
16 Pawlikowska L, Strautnieks S, Jankowska I. , et al. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol 2010; 53 (01) 170-178
17 Sambrotta M, Strautnieks S, Papouli E. , et al; University of Washington Center for Mendelian Genomics. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet 2014; 46 (04) 326-328
18 Gomez-Ospina N, Potter CJ, Xiao R. , et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun 2016; 7: 10713
19 Gonzales E, Taylor SA, Davit-Spraul A. , et al. MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease. Hepatology 2017; 65 (01) 164-173
20 Treepongkaruna S, Jitraruch S, Kodcharin P. , et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among Thai infants. BMC Gastroenterol 2012; 12: 141
21 Togawa T, Sugiura T, Ito K. , et al. Molecular genetic dissection and neonatal/infantile intrahepatic cholestasis using targeted next-generation sequencing. J Pediatr 2016; 171: 171-7.e1 , 4
22 Ohura T, Kobayashi K, Tazawa Y. , et al. Neonatal presentation of adult-onset type II citrullinemia. Hum Genet 2001; 108 (02) 87-90
23 Moghrabi N, Clarke DJ, Boxer M, Burchell B. Identification of an A-to-G missense mutation in exon 2 of the UGT1 gene complex that causes Crigler-Najjar syndrome type 2. Genomics 1993; 18 (01) 171-173
24 Koiwai O, Nishizawa M, Hasada K. , et al. Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. Hum Mol Genet 1995; 4 (07) 1183-1186
25 Kajihara S, Hisatomi A, Mizuta T. , et al. A splice mutation in the human canalicular multispecific organic anion transporter gene causes Dubin-Johnson syndrome. Biochem Biophys Res Commun 1998; 253 (02) 454-457
26 van de Steeg E, Stránecký V, Hartmannová H. , et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 2012; 122 (02) 519-528
27 Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009; 4 (07) 1073-1081
28 Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 2003; 31 (13) 3812-3814
29 Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 2013; ;Chapter 7: Unit 7.20
30 Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010; 7 (08) 575-576
31 Rastogi A, Krishnani N, Yachha SK, Khanna V, Poddar U, Lal R. Histopathological features and accuracy for diagnosing biliary atresia by prelaparotomy liver biopsy in developing countries. J Gastroenterol Hepatol 2009; 24 (01) 97-102
32 Moreira RK, Cabral R, Cowles RA, Lobritto SJ. Biliary atresia: a multidisciplinary approach to diagnosis and management. Arch Pathol Lab Med 2012; 136 (07) 746-760
33 Jacquemin E. Progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol 2012; 36 (Suppl. 01) S26-S35
34 Girard M, Lacaille F, Verkarre V. , et al. MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease. Hepatology 2014; 60 (01) 301-310
35 Piccoli DA, Spinner NB. Alagille syndrome and the Jagged1 gene. Semin Liver Dis 2001; 21 (04) 525-534
36 Kohsaka T, Yuan ZR, Guo SX. , et al. The significance of human jagged 1 mutations detected in severe cases of extrahepatic biliary atresia. Hepatology 2002; 36 (4 Pt 1): 904-912
37 Dědič T, Jirsa M, Keil R, Rygl M, Šnajdauf J, Kotalová R. Alagille syndrome mimicking biliary atresia in early infancy. PLoS One 2015; 10 (11) e0143939
38 Ohashi K, Togawa T, Sugiura T. , et al. Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome. Acta Paediatr 2017; 106 (11) 1817-1824
39 Lee SJ, Kim JE, Choe BH, Seo AN, Bae HI, Hwang SK. Early diagnosis of ABCB11 spectrum liver disorders by next generation sequencing. Pediatr Gastroenterol Hepatol Nutr 2017; 20 (02) 114-123
40 Fabre A, Roman C, Roquelaure B. Somatic mutation, a cause of biliary atresia: ahypothesis. Med Hypotheses 2017; 102: 91-93