Christophe Corpechot1,2, Véronique Barbu2,3, Olivier Chazouillères1,2, Pierre Broué4, Muriel Girard5,6, Bertrand Roquelaure7, Yves Chrétien1, Catherine Dong1, Olivier Lascols2,3, Chantal Housset1,2, Isabelle Jéru2,3. 1. Centre de Référence des Maladies Inflammatoires des Voies Biliaires et des Hépatites Auto-Immunes (MIVB-H), Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte (FILFOIE), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France. 2. INSERM, Centre de Recherche Saint-Antoine (CRSA), Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), Sorbonne Université, Paris, France. 3. Laboratoire Commun de Biologie et Génétique Moléculaires, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France. 4. Centres de compétences maladies rares du foie de l'enfant et Centre de référence constitutif maladies héréditaires du métabolisme, Hépatologie Pédiatrique et Maladies Héréditaires du Métabolisme, Hôpitaux de Toulouse, Hôpital des Enfants, Toulouse, France. 5. Service d'Hépato-Gastroentérologie et Nutrition Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France. 6. INSERM U1151, Institut Necker Enfants-Malades, Université Paris Descartes, Paris, France. 7. Service d'Hépato-Gastroentérologie et Nutrition Pédiatrique, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone Enfants, Marseille, France.
Abstract
BACKGROUND AND AIMS: The ABCC2 gene is implicated in Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders. METHODS: The cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP) and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next-generation sequencing. RESULTS: Most patients with clinical DJS had positive genetic diagnosis (n = 30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, eight (27%) of these patients showed transient cholestatic features at presentation: four neonatal cholestasis, two ICP, one contraceptive-induced cholestasis and one sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population. CONCLUSIONS: This large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.
BACKGROUND AND AIMS: The ABCC2 gene is implicated in Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders. METHODS: The cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP) and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next-generation sequencing. RESULTS: Most patients with clinical DJS had positive genetic diagnosis (n = 30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, eight (27%) of these patients showed transient cholestatic features at presentation: four neonatal cholestasis, two ICP, one contraceptive-induced cholestasis and one sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population. CONCLUSIONS: This large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.
Authors: Fatemeh Alaei Faradonbeh; Hana Lastuvkova; Jolana Cermanova; Milos Hroch; Zuzana Nova; Martin Uher; Petra Hirsova; Petr Pavek; Stanislav Micuda Journal: Front Physiol Date: 2022-03-21 Impact factor: 4.755