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 -