Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients

Christian Staufner; Bianca Peters; Matias Wagner; Seham Alameer; Ivo Barić; Pierre Broué; Derya Bulut; Joseph A. Church; Ellen Crushell; Buket Dalgıç; Anibh M. Das; Anke Dick; Nicola Dikow; Carlo Dionisi-Vici; Felix Distelmaier; Neslihan Ekşi Bozbulut; François Feillet; Emmanuel Gonzales; Nedim Hadzic; Fabian Hauck; Robert Hegarty; Maja Hempel; Theresia Herget; Christoph Klein; Vassiliki Konstantopoulou; Robert Kopajtich; Alice Kuster; Martin W. Laass; Elke Lainka; Catherine Larson-Nath; Alexander Leibner; Eberhard Lurz; Johannes A. Mayr; Patrick McKiernan; Karine Mention; Ute Moog; Neslihan Onenli Mungan; Korbinian M. Riedhammer; René Santer; Irene Valenzuela Palafoll; Jerry Vockley; Dominik S. Westphal; Arnaud Wiedemann; Saskia B. Wortmann; Gaurav D. Diwan; Robert B. Russell; Holger Prokisch; Sven F. Garbade; Stefan Kölker; Georg F. Hoffmann; Dominic Lenz

doi:10.1038/s41436-019-0698-4

Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients

Christian Staufner, Bianca Peters, Matias Wagner, Seham Alameer, Ivo Barić, Pierre Broué, Derya Bulut, Joseph A. Church, Ellen Crushell, Buket Dalgıç, Anibh M. Das, Anke Dick, Nicola Dikow, Carlo Dionisi-Vici, Felix Distelmaier, Neslihan Ekşi Bozbulut, François Feillet, Emmanuel Gonzales, Nedim Hadzic, Fabian HauckRobert Hegarty, Maja Hempel, Theresia Herget, Christoph Klein, Vassiliki Konstantopoulou, Robert Kopajtich, Alice Kuster, Martin W. Laass, Elke Lainka, Catherine Larson-Nath, Alexander Leibner, Eberhard Lurz, Johannes A. Mayr, Patrick McKiernan, Karine Mention, Ute Moog, Neslihan Onenli Mungan, Korbinian M. Riedhammer, René Santer, Irene Valenzuela Palafoll, Jerry Vockley, Dominik S. Westphal, Arnaud Wiedemann, Saskia B. Wortmann, Gaurav D. Diwan, Robert B. Russell, Holger Prokisch, Sven F. Garbade, Stefan Kölker, Georg F. Hoffmann, Dominic Lenz

Pediatric Gastroenterology, Hepatology & Nutrition

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

52 Scopus citations

Abstract

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Huët anomaly/SOPH). Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

Original language	English (US)
Pages (from-to)	610-621
Number of pages	12
Journal	Genetics in Medicine
Volume	22
Issue number	3
DOIs	https://doi.org/10.1038/s41436-019-0698-4
State	Published - Mar 1 2020

Bibliographical note

Publisher Copyright:
© 2019, American College of Medical Genetics and Genomics.

Keywords

NBAS
RALF
SOPH syndrome
acute liver failure
infantile liver failure syndrome type 2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41436-019-0698-4

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Staufner, C., Peters, B., Wagner, M., Alameer, S., Barić, I., Broué, P., Bulut, D., Church, J. A., Crushell, E., Dalgıç, B., Das, A. M., Dick, A., Dikow, N., Dionisi-Vici, C., Distelmaier, F., Bozbulut, N. E., Feillet, F., Gonzales, E., Hadzic, N., ... Lenz, D. (2020). Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients. Genetics in Medicine, 22(3), 610-621. https://doi.org/10.1038/s41436-019-0698-4

Staufner, C, Peters, B, Wagner, M, Alameer, S, Barić, I, Broué, P, Bulut, D, Church, JA, Crushell, E, Dalgıç, B, Das, AM, Dick, A, Dikow, N, Dionisi-Vici, C, Distelmaier, F, Bozbulut, NE, Feillet, F, Gonzales, E, Hadzic, N, Hauck, F, Hegarty, R, Hempel, M, Herget, T, Klein, C, Konstantopoulou, V, Kopajtich, R, Kuster, A, Laass, MW, Lainka, E, Larson-Nath, C, Leibner, A, Lurz, E, Mayr, JA, McKiernan, P, Mention, K, Moog, U, Mungan, NO, Riedhammer, KM, Santer, R, Palafoll, IV, Vockley, J, Westphal, DS, Wiedemann, A, Wortmann, SB, Diwan, GD, Russell, RB, Prokisch, H, Garbade, SF, Kölker, S, Hoffmann, GF & Lenz, D 2020, 'Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients', Genetics in Medicine, vol. 22, no. 3, pp. 610-621. https://doi.org/10.1038/s41436-019-0698-4

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title = "Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients",

abstract = "Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Hu{\"e}t anomaly/SOPH). Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.",

keywords = "NBAS, RALF, SOPH syndrome, acute liver failure, infantile liver failure syndrome type 2",

author = "Christian Staufner and Bianca Peters and Matias Wagner and Seham Alameer and Ivo Bari{\'c} and Pierre Brou{\'e} and Derya Bulut and Church, {Joseph A.} and Ellen Crushell and Buket Dalgı{\c c} and Das, {Anibh M.} and Anke Dick and Nicola Dikow and Carlo Dionisi-Vici and Felix Distelmaier and Bozbulut, {Neslihan Ek{\c s}i} and Fran{\c c}ois Feillet and Emmanuel Gonzales and Nedim Hadzic and Fabian Hauck and Robert Hegarty and Maja Hempel and Theresia Herget and Christoph Klein and Vassiliki Konstantopoulou and Robert Kopajtich and Alice Kuster and Laass, {Martin W.} and Elke Lainka and Catherine Larson-Nath and Alexander Leibner and Eberhard Lurz and Mayr, {Johannes A.} and Patrick McKiernan and Karine Mention and Ute Moog and Mungan, {Neslihan Onenli} and Riedhammer, {Korbinian M.} and Ren{\'e} Santer and Palafoll, {Irene Valenzuela} and Jerry Vockley and Westphal, {Dominik S.} and Arnaud Wiedemann and Wortmann, {Saskia B.} and Diwan, {Gaurav D.} and Russell, {Robert B.} and Holger Prokisch and Garbade, {Sven F.} and Stefan K{\"o}lker and Hoffmann, {Georg F.} and Dominic Lenz",

note = "Publisher Copyright: {\textcopyright} 2019, American College of Medical Genetics and Genomics.",

year = "2020",

month = mar,

day = "1",

doi = "10.1038/s41436-019-0698-4",

language = "English (US)",

volume = "22",

pages = "610--621",

journal = "Genetics in Medicine",

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T1 - Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients

AU - Staufner, Christian

AU - Peters, Bianca

AU - Wagner, Matias

AU - Alameer, Seham

AU - Barić, Ivo

AU - Broué, Pierre

AU - Bulut, Derya

AU - Church, Joseph A.

AU - Crushell, Ellen

AU - Dalgıç, Buket

AU - Das, Anibh M.

AU - Dick, Anke

AU - Dikow, Nicola

AU - Dionisi-Vici, Carlo

AU - Distelmaier, Felix

AU - Bozbulut, Neslihan Ekşi

AU - Feillet, François

AU - Gonzales, Emmanuel

AU - Hadzic, Nedim

AU - Hauck, Fabian

AU - Hegarty, Robert

AU - Hempel, Maja

AU - Herget, Theresia

AU - Klein, Christoph

AU - Konstantopoulou, Vassiliki

AU - Kopajtich, Robert

AU - Kuster, Alice

AU - Laass, Martin W.

AU - Lainka, Elke

AU - Larson-Nath, Catherine

AU - Leibner, Alexander

AU - Lurz, Eberhard

AU - Mayr, Johannes A.

AU - McKiernan, Patrick

AU - Mention, Karine

AU - Moog, Ute

AU - Mungan, Neslihan Onenli

AU - Riedhammer, Korbinian M.

AU - Santer, René

AU - Palafoll, Irene Valenzuela

AU - Vockley, Jerry

AU - Westphal, Dominik S.

AU - Wiedemann, Arnaud

AU - Wortmann, Saskia B.

AU - Diwan, Gaurav D.

AU - Russell, Robert B.

AU - Prokisch, Holger

AU - Garbade, Sven F.

AU - Kölker, Stefan

AU - Hoffmann, Georg F.

AU - Lenz, Dominic

PY - 2020/3/1

Y1 - 2020/3/1

N2 - Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Huët anomaly/SOPH). Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

AB - Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Huët anomaly/SOPH). Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

KW - NBAS

KW - RALF

KW - SOPH syndrome

KW - acute liver failure

KW - infantile liver failure syndrome type 2

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Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

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