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


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.

Bibliographical data

Original languageEnglish
Publication statusPublished - 03.2020
PubMed 31761904