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Genet Med. 2019 Nov 25. doi: 10.1038/s41436-019-0698-4. [Epub ahead of print]

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

Author information

1
Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
2
Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Munich, Germany.
3
Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany.
4
Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
5
Department of Pediatrics, King Khaled National Guard Hospital, Jeddah, Saudi Arabia.
6
Department of Pediatrics, University Hospital Center Zagreb and University of Zagreb, School of Medicine, Zagreb, Croatia.
7
Pediatric Gastroenterology, Hepatology and Nutrition unit, Reference Center for Inherited Metabolic Diseases, Children's Hospital, Toulouse University Hospital, Toulouse, France.
8
Cukurova University Medical Faculty, Department of Pediatric Metabolism, Adana, Turkey.
9
Department of Pediatrics, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, USA.
10
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
11
Gazi University Faculty of Medicine, Department of Pediatric Gastroenterology, Ankara, Turkey.
12
Clinic for Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
13
Department of Pediatrics, University Hospital Würzburg, Wuerzburg, Germany.
14
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
15
Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy.
16
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
17
Department of Pediatrics, INSERM 1256, Hôpital d'Enfants Brabois, CHU Nancy, Vandoeuvre les Nancy, France.
18
Pediatric Hepatology and Pediatric Liver Transplantation Unit, Bicêtre Hospital, AP-HP Paris-Sud University, Le Kremlin-Bicêtre, France.
19
Pediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, UK.
20
Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
21
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
22
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
23
Inborn Errors of Metabolism, Pediatric Intensive Care Unit, University Hospital of Nantes, Nantes, France.
24
Children's Hospital, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
25
Children's Hospital, Department of Pediatric Gastroenterology, Hepatology, and Transplant Medicine, University Duisburg-Essen, Essen, Germany.
26
Pediatric Gastroenterology, University of Minnesota Medical School, Minneapolis, MN, USA.
27
Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.
28
University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
29
Reference Center for Inherited Metabolic Diseases, Jeanne de Flandres Hospital, Lille, France.
30
Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
31
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
32
Department of Clinical Genetics and Molecular Genetics, Hospital Vall d'Hebron, Barcelona, Spain.
33
CellNetworks, Bioquant, Heidelberg University, Heidelberg, Germany.
34
Biochemie Zentrum Heidelberg (BZH), Heidelberg University, Heidelberg, Germany.
35
Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. Dominic.Lenz@med.uni-heidelberg.de.

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.

KEYWORDS:

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

PMID:
31761904
DOI:
10.1038/s41436-019-0698-4

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