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

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Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.
Genetics in Medicine ( IF 8.8 ) Pub Date : 2019-11-25 , DOI: 10.1038/s41436-019-0698-4
Christian Staufner ₁ , Bianca Peters ₁ , Matias Wagner _{2,

3,

4} , Seham Alameer ₅ , Ivo Barić ₆ , Pierre Broué ₇ , Derya Bulut ₈ , Joseph A Church ₉ , Ellen Crushell ₁₀ , Buket Dalgıç ₁₁ , Anibh M Das ₁₂ , Anke Dick ₁₃ , Nicola Dikow ₁₄ , Carlo Dionisi-Vici ₁₅ , Felix Distelmaier ₁₆ , Neslihan Ekşi Bozbulut ₁₁ , François Feillet ₁₇ , Emmanuel Gonzales ₁₈ , Nedim Hadzic ₁₉ , Fabian Hauck ₂₀ , Robert Hegarty ₁₉ , Maja Hempel ₂₁ , Theresia Herget ₂₁ , Christoph Klein ₂₀ , Vassiliki Konstantopoulou ₂₂ , Robert Kopajtich _{2,

3} , Alice Kuster ₂₃ , Martin W Laass ₂₄ , Elke Lainka ₂₅ , Catherine Larson-Nath ₂₆ , Alexander Leibner ₁ , Eberhard Lurz ₂₀ , Johannes A Mayr ₂₇ , Patrick McKiernan ₂₈ , Karine Mention ₂₉ , Ute Moog ₁₄ , Neslihan Onenli Mungan ₈ , Korbinian M Riedhammer _{2,

3,

30} , René Santer ₃₁ , Irene Valenzuela Palafoll ₃₂ , Jerry Vockley ₂₈ , Dominik S Westphal _{2,

3} , Arnaud Wiedemann ₁₇ , Saskia B Wortmann _{2,

3,

27} , Gaurav D Diwan _{33,

34} , Robert B Russell _{33,

34} , Holger Prokisch _{2,

3} , Sven F Garbade ₁ , Stefan Kölker ₁ , Georg F Hoffmann ₁ , Dominic Lenz ₁

Affiliation

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

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.

中文翻译：

在 110 名患者中定义 NBAS 相关疾病的临床亚组和基因型-表型相关性。

目的

神经母细胞瘤扩增序列 ( NBAS ) 中的致病性变异会导致一种常染色体隐性遗传疾病，其症状范围广泛，影响肝脏、骨骼系统和大脑等。患者数量不断增加，但缺乏系统和定量分析。

方法

在一项国际多中心研究中招募了NBAS中具有双等位基因变异的个体，包括新的和先前发表的患者。使用对数线性模型分析临床变量并通过马赛克图进行可视化；通过 DeepGestalt 研究面部轮廓。使用计算方法预测 NBAS 蛋白的结构。

结果

鉴定了来自 97 个家族的 110 个具有双等位基因致病性NBAS变异的个体，其中包括 26 名新患者，具有 19 个以前未报告的变异，总共有 86 个变异。蛋白质建模重新定义了 NBAS 的 β-螺旋桨结构域。基于错义变异和框内缺失的定位，出现了三个临床亚组，它们在主要临床特征方面存在显着差异，并且与 NBAS 蛋白的受影响区域直接相关：β-螺旋桨（组合表型）、Sec39（婴儿肝衰竭）综合征类型 2/ILFS2）和 C 末端（身材矮小、视神经萎缩和 Pelger-Huët 异常/SOPH）。