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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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 languageEnglish (US)
Pages (from-to)610-621
Number of pages12
JournalGenetics in Medicine
Issue number3
StatePublished - Mar 1 2020

Bibliographical note

Funding Information:
We thank Yoo-Mi Kim for providing additional, updated clinical information on patients NBAS 42 and NBAS 43 and John Christodoulou and Shanti Balasubramaniam for providing additional, updated clinical information on patient NBAS 63. Anne Davit Spraul is acknowledged for genetic diagnosis of patients NBAS 46 and NBAS 82, Oanez Ackermann and Dalila Habes are acknowledged for follow-up and Philippe Yakonowsky for his contribution to data collection of these patients. We thank Selina Wächter and Caterina Terrile for excellent technical assistance and Katharina Mayerhanser for organizational support. C.S. is supported by the Dietmar Hopp Foundation, St. Leon-Rot, Germany (grant number 23011235). D.L. is supported by the Deutsche Leberstiftung (grant number S163/10052/2018). J.A.C. is supported in part by the Jeffrey Model Foundation. R.B.R. and G.D.D. are supported by the Wellcome Trust grant 210585/B/18/Z (Impact of missense mutations in recessive Mendelian disease: insight from ciliopathies).

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


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


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