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-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.

• Authors: 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
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 22 Issue 3 Pg. 610-621 (03 2020) ISSN: 1530-0366 [Electronic] United States
• PMID: 31761904 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NBAS protein, human
• Neoplasm Proteins

Topics

• Alleles
• Brain (pathology)
• Child
• Child, Preschool
• Female
• Genetic Diseases, Inborn (genetics, pathology)
• Genetic Predisposition to Disease
• Humans
• Infant
• Liver (pathology)
• Liver Transplantation (adverse effects)
• Male
• Muscle, Skeletal (pathology)
• Mutation, Missense (genetics)
• Neoplasm Proteins (genetics)
• Phenotype