Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children with Monogenic Cholestasis

Paula M. Hertel; Laura N. Bull; Richard J. Thompson; Nathan P. Goodrich; Wen Ye; John C. Magee; Robert H. Squires; Lee M. Bass; James E. Heubi; Grace E. Kim; Sarangarajan Ranganathan; Kathleen B. Schwarz; Molly A. Bozic; Simon P. Horslen; Matthew S. Clifton; Yumirle P. Turmelle; Frederick J. Suchy; Riccardo A. Superina; Kasper S. Wang; Kathleen M. Loomes; Binita M. Kamath; Ronald J. Sokol; Benjamin L. Shneider

doi:10.1097/MPG.0000000000003153

Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children with Monogenic Cholestasis

Paula M. Hertel^*, Laura N. Bull, Richard J. Thompson, Nathan P. Goodrich, Wen Ye, John C. Magee, Robert H. Squires, Lee M. Bass, James E. Heubi, Grace E. Kim, Sarangarajan Ranganathan, Kathleen B. Schwarz, Molly A. Bozic, Simon P. Horslen, Matthew S. Clifton, Yumirle P. Turmelle, Frederick J. Suchy, Riccardo A. Superina, Kasper S. Wang, Kathleen M. LoomesBinita M. Kamath, Ronald J. Sokol, Benjamin L. Shneider

^*Corresponding author for this work

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

9 Scopus citations

Abstract

Objectives:To advance our understanding of monogenic forms of intrahepatic cholestasis.Methods:Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.Results:Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.Conclusions:In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

Original language	English (US)
Pages (from-to)	169-177
Number of pages	9
Journal	Journal of pediatric gastroenterology and nutrition
Volume	73
Issue number	2
DOIs	https://doi.org/10.1097/MPG.0000000000003153
State	Published - Aug 1 2021

Funding

Sources of Funding: This work was supported by U01 grants from the National Institute of Diabetes, Digestive and Kidney Diseases (DK062445 [Mt. Sinai School of Medicine], DK062497 [Cincinnati Children's Hospital Medical Center], DK062470 [Children's Healthcare of Atlanta], DK062481 [The Children's Hospital of Philadelphia], DK062456 [The University of Michigan], DK084536 [Riley Hospital for Children], DK084575 [Seattle Children's Hospital], DK062500 [UCSF Children's Hospital], DK062466 [Children's Hospital of Pittsburgh of UPMC], DK062453 [Children's Hospital Colorado], DK084538 [Children's Hospital Los Angeles], DK062436 [Ann & Robert H Lurie Children's Hospital of Chicago], DK103149 [Texas Children's Hospital], DK103135 [The Hospital for Sick Children], DK103140 [University of Utah]). Conflicts of Interest: R.J.T. consults for Albireo Pharma, Alnylam, EVOX Therapeutics, GenerationBio, Horizon Pharma, Mirum Pharma, Qing Bile Therapeutics, Retrophin, and Sana Biotechnology. He has shared options in GenerationBio and Qing Bile Therapeutics. S.P.H. reports participation in the Mirum maralixibat PFIC trials—research grants only paid to the institution. M.S.C. reports participation in the Bolder Surgical, Inc. (Louisville, CO) Physician Advisory Board. K.M.L. declares consulting relationships and research grants from Mirum Pharmaceuticals and Albireo Pharma. B.M.K. reports she is a consultant and has unrestricted educational grants from Albireo and Mirum. For all remaining coauthors, no conflicts of interest are declared. In addition, the project described was supported by the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (NCATS CTSA) grants: University of Colorado UL1 TR002535, UCSF Children s Hospital UL1 TR001872, Children s Hospital of Pittsburgh of UPMC UL1 TR001857, The Children s Hospital of Philadelphia UL1 TR001878, Seattle Children s Hospital UL1 TR000423 and UL1 RR025014, Children s Healthcare of Atlanta UL1TR002378, Children s Hospital of Los Angeles UL1TR00130. In addition, the project described was supported by the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (NCATS CTSA) grants: University of Colorado UL1 TR002535, UCSF Children's Hospital UL1 TR001872, Children's Hospital of Pittsburgh of UPMC UL1 TR001857, The Children's Hospital of Philadelphia UL1 TR001878, Seattle Children's Hospital UL1 TR000423 and UL1 RR025014, Children's Healthcare of Atlanta UL1TR002378, Children's Hospital of Los Angeles UL1TR00130.

Keywords

adenosine triphosphatase (ATPase) phospholipid transporting 8B1
adenosine triphosphate (ATP)-binding cassette subfamily B member 11
adenosine triphosphate (ATP)-binding cassette subfamily B member 4
cholestasis
liver transplant

ASJC Scopus subject areas

Gastroenterology
Pediatrics, Perinatology, and Child Health

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10.1097/MPG.0000000000003153

Cite this

Hertel, P. M., Bull, L. N., Thompson, R. J., Goodrich, N. P., Ye, W., Magee, J. C., Squires, R. H., Bass, L. M., Heubi, J. E., Kim, G. E., Ranganathan, S., Schwarz, K. B., Bozic, M. A., Horslen, S. P., Clifton, M. S., Turmelle, Y. P., Suchy, F. J., Superina, R. A., Wang, K. S., ... Shneider, B. L. (2021). Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children with Monogenic Cholestasis. Journal of pediatric gastroenterology and nutrition, 73(2), 169-177. https://doi.org/10.1097/MPG.0000000000003153

@article{606962532c624ffb961df728b9aac4ea,

title = "Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children with Monogenic Cholestasis",

abstract = "Objectives:To advance our understanding of monogenic forms of intrahepatic cholestasis.Methods:Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.Results:Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.Conclusions:In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.",

keywords = "adenosine triphosphatase (ATPase) phospholipid transporting 8B1, adenosine triphosphate (ATP)-binding cassette subfamily B member 11, adenosine triphosphate (ATP)-binding cassette subfamily B member 4, cholestasis, liver transplant",

author = "Hertel, {Paula M.} and Bull, {Laura N.} and Thompson, {Richard J.} and Goodrich, {Nathan P.} and Wen Ye and Magee, {John C.} and Squires, {Robert H.} and Bass, {Lee M.} and Heubi, {James E.} and Kim, {Grace E.} and Sarangarajan Ranganathan and Schwarz, {Kathleen B.} and Bozic, {Molly A.} and Horslen, {Simon P.} and Clifton, {Matthew S.} and Turmelle, {Yumirle P.} and Suchy, {Frederick J.} and Superina, {Riccardo A.} and Wang, {Kasper S.} and Loomes, {Kathleen M.} and Kamath, {Binita M.} and Sokol, {Ronald J.} and Shneider, {Benjamin L.}",

note = "Funding Information: Sources of Funding: This work was supported by U01 grants from the National Institute of Diabetes, Digestive and Kidney Diseases (DK062445 [Mt. Sinai School of Medicine], DK062497 [Cincinnati Children's Hospital Medical Center], DK062470 [Children's Healthcare of Atlanta], DK062481 [The Children's Hospital of Philadelphia], DK062456 [The University of Michigan], DK084536 [Riley Hospital for Children], DK084575 [Seattle Children's Hospital], DK062500 [UCSF Children's Hospital], DK062466 [Children's Hospital of Pittsburgh of UPMC], DK062453 [Children's Hospital Colorado], DK084538 [Children's Hospital Los Angeles], DK062436 [Ann & Robert H Lurie Children's Hospital of Chicago], DK103149 [Texas Children's Hospital], DK103135 [The Hospital for Sick Children], DK103140 [University of Utah]). Funding Information: Conflicts of Interest: R.J.T. consults for Albireo Pharma, Alnylam, EVOX Therapeutics, GenerationBio, Horizon Pharma, Mirum Pharma, Qing Bile Therapeutics, Retrophin, and Sana Biotechnology. He has shared options in GenerationBio and Qing Bile Therapeutics. S.P.H. reports participation in the Mirum maralixibat PFIC trials—research grants only paid to the institution. M.S.C. reports participation in the Bolder Surgical, Inc. (Louisville, CO) Physician Advisory Board. K.M.L. declares consulting relationships and research grants from Mirum Pharmaceuticals and Albireo Pharma. B.M.K. reports she is a consultant and has unrestricted educational grants from Albireo and Mirum. For all remaining coauthors, no conflicts of interest are declared. Funding Information: In addition, the project described was supported by the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (NCATS CTSA) grants: University of Colorado UL1 TR002535, UCSF Children s Hospital UL1 TR001872, Children s Hospital of Pittsburgh of UPMC UL1 TR001857, The Children s Hospital of Philadelphia UL1 TR001878, Seattle Children s Hospital UL1 TR000423 and UL1 RR025014, Children s Healthcare of Atlanta UL1TR002378, Children s Hospital of Los Angeles UL1TR00130. Funding Information: In addition, the project described was supported by the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (NCATS CTSA) grants: University of Colorado UL1 TR002535, UCSF Children's Hospital UL1 TR001872, Children's Hospital of Pittsburgh of UPMC UL1 TR001857, The Children's Hospital of Philadelphia UL1 TR001878, Seattle Children's Hospital UL1 TR000423 and UL1 RR025014, Children's Healthcare of Atlanta UL1TR002378, Children's Hospital of Los Angeles UL1TR00130. Publisher Copyright: {\textcopyright} 2021 Lippincott Williams and Wilkins. All rights reserved.",

year = "2021",

month = aug,

day = "1",

doi = "10.1097/MPG.0000000000003153",

language = "English (US)",

volume = "73",

pages = "169--177",

journal = "Journal of pediatric gastroenterology and nutrition",

issn = "0277-2116",

publisher = "Lippincott Williams and Wilkins",

number = "2",

}

Hertel, PM, Bull, LN, Thompson, RJ, Goodrich, NP, Ye, W, Magee, JC, Squires, RH, Bass, LM, Heubi, JE, Kim, GE, Ranganathan, S, Schwarz, KB, Bozic, MA, Horslen, SP, Clifton, MS, Turmelle, YP, Suchy, FJ, Superina, RA, Wang, KS, Loomes, KM, Kamath, BM, Sokol, RJ & Shneider, BL 2021, 'Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children with Monogenic Cholestasis', Journal of pediatric gastroenterology and nutrition, vol. 73, no. 2, pp. 169-177. https://doi.org/10.1097/MPG.0000000000003153

TY - JOUR

T1 - Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children with Monogenic Cholestasis

AU - Hertel, Paula M.

AU - Bull, Laura N.

AU - Thompson, Richard J.

AU - Goodrich, Nathan P.

AU - Ye, Wen

AU - Magee, John C.

AU - Squires, Robert H.

AU - Bass, Lee M.

AU - Heubi, James E.

AU - Kim, Grace E.

AU - Ranganathan, Sarangarajan

AU - Schwarz, Kathleen B.

AU - Bozic, Molly A.

AU - Horslen, Simon P.

AU - Clifton, Matthew S.

AU - Turmelle, Yumirle P.

AU - Suchy, Frederick J.

AU - Superina, Riccardo A.

AU - Wang, Kasper S.

AU - Loomes, Kathleen M.

AU - Kamath, Binita M.

AU - Sokol, Ronald J.

AU - Shneider, Benjamin L.

N1 - Funding Information: Sources of Funding: This work was supported by U01 grants from the National Institute of Diabetes, Digestive and Kidney Diseases (DK062445 [Mt. Sinai School of Medicine], DK062497 [Cincinnati Children's Hospital Medical Center], DK062470 [Children's Healthcare of Atlanta], DK062481 [The Children's Hospital of Philadelphia], DK062456 [The University of Michigan], DK084536 [Riley Hospital for Children], DK084575 [Seattle Children's Hospital], DK062500 [UCSF Children's Hospital], DK062466 [Children's Hospital of Pittsburgh of UPMC], DK062453 [Children's Hospital Colorado], DK084538 [Children's Hospital Los Angeles], DK062436 [Ann & Robert H Lurie Children's Hospital of Chicago], DK103149 [Texas Children's Hospital], DK103135 [The Hospital for Sick Children], DK103140 [University of Utah]). Funding Information: Conflicts of Interest: R.J.T. consults for Albireo Pharma, Alnylam, EVOX Therapeutics, GenerationBio, Horizon Pharma, Mirum Pharma, Qing Bile Therapeutics, Retrophin, and Sana Biotechnology. He has shared options in GenerationBio and Qing Bile Therapeutics. S.P.H. reports participation in the Mirum maralixibat PFIC trials—research grants only paid to the institution. M.S.C. reports participation in the Bolder Surgical, Inc. (Louisville, CO) Physician Advisory Board. K.M.L. declares consulting relationships and research grants from Mirum Pharmaceuticals and Albireo Pharma. B.M.K. reports she is a consultant and has unrestricted educational grants from Albireo and Mirum. For all remaining coauthors, no conflicts of interest are declared. Funding Information: In addition, the project described was supported by the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (NCATS CTSA) grants: University of Colorado UL1 TR002535, UCSF Children s Hospital UL1 TR001872, Children s Hospital of Pittsburgh of UPMC UL1 TR001857, The Children s Hospital of Philadelphia UL1 TR001878, Seattle Children s Hospital UL1 TR000423 and UL1 RR025014, Children s Healthcare of Atlanta UL1TR002378, Children s Hospital of Los Angeles UL1TR00130. Funding Information: In addition, the project described was supported by the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (NCATS CTSA) grants: University of Colorado UL1 TR002535, UCSF Children's Hospital UL1 TR001872, Children's Hospital of Pittsburgh of UPMC UL1 TR001857, The Children's Hospital of Philadelphia UL1 TR001878, Seattle Children's Hospital UL1 TR000423 and UL1 RR025014, Children's Healthcare of Atlanta UL1TR002378, Children's Hospital of Los Angeles UL1TR00130. Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.

PY - 2021/8/1

Y1 - 2021/8/1

N2 - Objectives:To advance our understanding of monogenic forms of intrahepatic cholestasis.Methods:Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.Results:Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.Conclusions:In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

AB - Objectives:To advance our understanding of monogenic forms of intrahepatic cholestasis.Methods:Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.Results:Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.Conclusions:In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

KW - adenosine triphosphatase (ATPase) phospholipid transporting 8B1

KW - adenosine triphosphate (ATP)-binding cassette subfamily B member 11

KW - adenosine triphosphate (ATP)-binding cassette subfamily B member 4

KW - cholestasis

KW - liver transplant

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U2 - 10.1097/MPG.0000000000003153

DO - 10.1097/MPG.0000000000003153

M3 - Article

C2 - 34016879

AN - SCOPUS:85114522545

SN - 0277-2116

VL - 73

SP - 169

EP - 177

JO - Journal of pediatric gastroenterology and nutrition

JF - Journal of pediatric gastroenterology and nutrition

IS - 2

ER -

Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children with Monogenic Cholestasis

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