Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium; Antonia Felzen; Daan B.E. van Wessel; Emmanuel Gonzales; Richard J. Thompson; Irena Jankowska; Benjamin L. Shneider; Etienne Sokal; Tassos Grammatikopoulos; Agustina Kadaristiana; Emmanuel Jacquemin; Anne Spraul; Patryk Lipiński; Piotr Czubkowski; Nathalie Rock; Mohammad Shagrani; Dieter Broering; Emanuele Nicastro; Deirdre Kelly; Gabriella Nebbia; Henrik Arnell; Björn Fischler; Jan B.F. Hulscher; Daniele Serranti; Cigdem Arikan; Esra Polat; Dominique Debray; Florence Lacaille; Cristina Goncalves; 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 Fischer; Carolina Jimenez-Rivera; Seema Alam; Mara Cananzi; Noemie 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 J McKiernan; Philip Rosenthal; Yumirle Turmelle; Simon Horslen; Kathleen Schwarz; Jorge A Bezerra; Kasper Wang; Bettina E. Hansen; Henkjan Verkade

doi:10.1016/j.jhepr.2022.100626

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium, Antonia Felzen, Daan B.E. van Wessel, Emmanuel Gonzales, Richard J. Thompson, Irena Jankowska, Benjamin L. Shneider, Etienne Sokal, Tassos Grammatikopoulos, Agustina Kadaristiana, Emmanuel Jacquemin, Anne Spraul, Patryk Lipiński, Piotr Czubkowski, Nathalie Rock, Mohammad Shagrani, Dieter Broering, Emanuele Nicastro, Deirdre Kelly, Gabriella NebbiaHenrik Arnell, Björn Fischler, Jan B.F. Hulscher, Daniele Serranti, Cigdem Arikan, Esra Polat, Dominique Debray, Florence Lacaille, Cristina Goncalves, 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 Fischer, Carolina Jimenez-Rivera, Seema Alam, Mara Cananzi, Noemie 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 J McKiernan, Philip Rosenthal, Yumirle Turmelle, Simon Horslen, Kathleen Schwarz, Jorge A Bezerra, Kasper Wang, Bettina E. Hansen, Henkjan Verkade^*

^*Corresponding author for this work

Center for Liver, Digestive and Metabolic Diseases (CLDM)

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Abstract

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). 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 presentation, native liver survival (NLS), and effect of siEHC on NLS.

Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001).

Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients 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.

Original language	English
Article number	100626
Number of pages	12
Journal	JHEP reports : innovation in hepatology
Volume	5
Issue number	2
DOIs	https://doi.org/10.1016/j.jhepr.2022.100626
Publication status	Published - Feb-2023

Keywords

BSEP
PFIC2
COMPOUND HETEROZYGOSITY
interruption of the enterohepatic circulation
genotype
phenotype

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NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium, Felzen, A., van Wessel, D. B. E., Gonzales, E., Thompson, R. J., Jankowska, I., Shneider, B. L., Sokal, E., Grammatikopoulos, T., Kadaristiana, A., Jacquemin, E., Spraul, A., Lipiński, P., Czubkowski, P., Rock, N., Shagrani, M., Broering, D., Nicastro, E., Kelly, D., ... Verkade, H. (2023). Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. JHEP reports : innovation in hepatology, 5(2), Article 100626. https://doi.org/10.1016/j.jhepr.2022.100626

@article{8ef0e969bbb84a92b0d89e96e4c99c90,

title = "Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency",

abstract = "Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). 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 presentation, native liver survival (NLS), and effect of siEHC on NLS.Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001).Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients 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.",

keywords = "BSEP, PFIC2, COMPOUND HETEROZYGOSITY, interruption of the enterohepatic circulation, genotype, phenotype",

author = "{NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium} and Antonia Felzen and {van Wessel}, {Daan B.E.} and Emmanuel Gonzales and Thompson, {Richard J.} and Irena Jankowska and Shneider, {Benjamin L.} and Etienne Sokal and Tassos Grammatikopoulos and Agustina Kadaristiana and Emmanuel Jacquemin and Anne Spraul and Patryk Lipi{\'n}ski and Piotr Czubkowski and Nathalie Rock and Mohammad Shagrani and Dieter Broering and Emanuele Nicastro and Deirdre Kelly and Gabriella Nebbia and Henrik Arnell and Bj{\"o}rn Fischler and Hulscher, {Jan B.F.} and Daniele Serranti and Cigdem Arikan and Esra Polat and Dominique Debray and Florence Lacaille and Cristina Goncalves and Loreto Hierro and {Mu{\~n}oz Bartolo}, Gema and Yael Mozer-Glassberg and Amer Azaz and Jernej Brecelj and Antal Dezs{\H o}fi and Calvo, {Pier Luigi} and Enke Grabhorn and Steffen Hartleif and {van der Woerd}, {Wendy J} and Kamath, {Binita M.} and Jian-She Wang and Liting Li and {\"O}zlem Durmaz and Nanda Kerkar and J{\o}rgensen, {Marianne H{\o}rby} and Ryan Fischer and Carolina Jimenez-Rivera and Seema Alam and Mara Cananzi and Noemie Laverdure and Ferreira, {Cristina Targa} and {Ordo{\~n}ez Guerrero}, Felipe and Heng Wang and Valerie Sency and Kim, {Kyung Mo} and Huey-Ling Chen and {de Carvalho}, Elisa and Alexandre Fabre and Bernabeu, {Jesus Quintero} and Aglaia Zellos and Alonso, {Estella M.} and Sokol, {Ronald J} and Suchy, {Frederick J.} and Loomes, {Kathleen M.} and McKiernan, {Patrick J} and Philip Rosenthal and Yumirle Turmelle and Simon Horslen and Kathleen Schwarz and Bezerra, {Jorge A} and Kasper Wang and Hansen, {Bettina E.} and Henkjan Verkade",

year = "2023",

month = feb,

doi = "10.1016/j.jhepr.2022.100626",

language = "English",

volume = "5",

journal = "JHEP reports : innovation in hepatology",

issn = "2589-5559",

publisher = "Elsevier",

number = "2",

}

NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium, Felzen, A , van Wessel, DBE, Gonzales, E, Thompson, RJ, Jankowska, I, Shneider, BL, Sokal, E, Grammatikopoulos, T, Kadaristiana, A, Jacquemin, E, Spraul, A, Lipiński, P, Czubkowski, P, Rock, N, Shagrani, M, Broering, D, Nicastro, E, Kelly, D, Nebbia, G, Arnell, H, Fischler, B, Hulscher, JBF, Serranti, D, Arikan, C, Polat, E, Debray, D, Lacaille, F, Goncalves, C, Hierro, L, Muñoz Bartolo, G, Mozer-Glassberg, Y, Azaz, A, Brecelj, J, Dezsőfi, A, Calvo, PL, Grabhorn, E, Hartleif, S, van der Woerd, WJ, Kamath, BM, Wang, J-S, Li, L, Durmaz, Ö, Kerkar, N, Jørgensen, MH, Fischer, R, Jimenez-Rivera, C, Alam, S, Cananzi, M, Laverdure, N, Ferreira, CT, Ordoñez Guerrero, F, Wang, H, Sency, V, Kim, KM, Chen, H-L, de Carvalho, E, Fabre, A, Bernabeu, JQ, Zellos, A, Alonso, EM, Sokol, RJ, Suchy, FJ, Loomes, KM, McKiernan, PJ, Rosenthal, P, Turmelle, Y, Horslen, S, Schwarz, K, Bezerra, JA, Wang, K, Hansen, BE & Verkade, H 2023, 'Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency', JHEP reports : innovation in hepatology, vol. 5, no. 2, 100626. https://doi.org/10.1016/j.jhepr.2022.100626

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. / NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium ; Felzen, Antonia ; van Wessel, Daan B.E. et al.
In: JHEP reports : innovation in hepatology, Vol. 5, No. 2, 100626, 02.2023.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

AU - NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium

AU - Felzen, Antonia

AU - van Wessel, Daan B.E.

AU - Gonzales, Emmanuel

AU - Thompson, Richard J.

AU - Jankowska, Irena

AU - Shneider, Benjamin L.

AU - Sokal, Etienne

AU - Grammatikopoulos, Tassos

AU - Kadaristiana, Agustina

AU - Jacquemin, Emmanuel

AU - Spraul, Anne

AU - Lipiński, Patryk

AU - Czubkowski, Piotr

AU - Rock, Nathalie

AU - Shagrani, Mohammad

AU - Broering, Dieter

AU - Nicastro, Emanuele

AU - Kelly, Deirdre

AU - Nebbia, Gabriella

AU - Arnell, Henrik

AU - Fischler, Björn

AU - Hulscher, Jan B.F.

AU - Serranti, Daniele

AU - Arikan, Cigdem

AU - Polat, Esra

AU - Debray, Dominique

AU - Lacaille, Florence

AU - Goncalves, Cristina

AU - Hierro, Loreto

AU - Muñoz Bartolo, Gema

AU - Mozer-Glassberg, Yael

AU - Azaz, Amer

AU - Brecelj, Jernej

AU - Dezsőfi, Antal

AU - Calvo, Pier Luigi

AU - Grabhorn, Enke

AU - Hartleif, Steffen

AU - van der Woerd, Wendy J

AU - Kamath, Binita M.

AU - Wang, Jian-She

AU - Li, Liting

AU - Durmaz, Özlem

AU - Kerkar, Nanda

AU - Jørgensen, Marianne Hørby

AU - Fischer, Ryan

AU - Jimenez-Rivera, Carolina

AU - Alam, Seema

AU - Cananzi, Mara

AU - Laverdure, Noemie

AU - Ferreira, Cristina Targa

AU - Ordoñez Guerrero, Felipe

AU - Wang, Heng

AU - Sency, Valerie

AU - Kim, Kyung Mo

AU - Chen, Huey-Ling

AU - de Carvalho, Elisa

AU - Fabre, Alexandre

AU - Bernabeu, Jesus Quintero

AU - Zellos, Aglaia

AU - Alonso, Estella M.

AU - Sokol, Ronald J

AU - Suchy, Frederick J.

AU - Loomes, Kathleen M.

AU - McKiernan, Patrick J

AU - Rosenthal, Philip

AU - Turmelle, Yumirle

AU - Horslen, Simon

AU - Schwarz, Kathleen

AU - Bezerra, Jorge A

AU - Wang, Kasper

AU - Hansen, Bettina E.

AU - Verkade, Henkjan

PY - 2023/2

Y1 - 2023/2

N2 - Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). 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 presentation, native liver survival (NLS), and effect of siEHC on NLS.Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001).Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients 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.

AB - Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). 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 presentation, native liver survival (NLS), and effect of siEHC on NLS.Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001).Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients 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.

KW - BSEP

KW - PFIC2

KW - COMPOUND HETEROZYGOSITY

KW - interruption of the enterohepatic circulation

KW - genotype

KW - phenotype

U2 - 10.1016/j.jhepr.2022.100626

DO - 10.1016/j.jhepr.2022.100626

M3 - Article

SN - 2589-5559

VL - 5

JO - JHEP reports : innovation in hepatology

JF - JHEP reports : innovation in hepatology

IS - 2

M1 - 100626

ER -

NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium, Felzen A , van Wessel DBE, Gonzales E, Thompson RJ, Jankowska I et al. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. JHEP reports : innovation in hepatology. 2023 Feb;5(2):100626. doi: 10.1016/j.jhepr.2022.100626

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

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