Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency
Antonia Felzen, Daan van Wessel, Emmanuel Gonzalès, Richard J. Thompson, Irena Jankowska, Benjamin L. Shneider, Étienne Sokal, Tassos Grammatikopoulos, Agustina Kadaristiana, Emmanuel Jacquemin, Anne Spraul, Patryk Lipiński, Piotr Czubkowski, Nathalie Rock, Mohammad Shagrani, Dieter C. Bröering, Emanuele Nicastro, Déirdre Kelly, Gabriella Nebbia, Henrik Arnell, Björn Fischler, Jan B.F. Hulscher, Daniele Serranti, Çiğdem Arıkan, Esra Polat, Dominique Debray, Florence Lacaille, Cristina Gonçalves, Loreto Hierro, Gema Muñoz Bartolo, Yael Mozer‐Glassberg, Amer Azaz, Jernej Brecelj, Antal Dezsőfi, Pier Luigi Calvo, Enke Grabhorn, Steffen Hartleif, Wendy J. van der Woerd, Binita M. Kamath, Jian‐She Wang, Liting Li, Özlem Durmaz, Nanda Kerkar, Marianne Hørby Jørgensen, Ryan T. Fischer, Carolina Jiménez‐Rivera, Seema Alam, Mara Cananzi, Noémie Laverdure, Cristina Targa Ferreira, Felipe Ordoñez Guerrero, Heng Wang, Valerie Sency, Kyung Mo Kim, Huey‐Ling Chen, Elisa de Carvalho, Alexandre Fabre, Jesus Quintero Bernabeu, Aglaia Zellos, Estella M. Alonso, Ronald J. Sokol, Frederick J. Suchy, Kathleen M. Loomes, Patrick McKiernan, Philip Rosenthal, Yumirle P. Turmelle, Simon Horslen, Kathleen B. Schwarz, Jorge A. Bezerra, Kasper Wang, Bettina E. Hansen, Henkjan J. Verkade
Abstract
Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: 0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.