Overlapping phenotypes between SHORT and Noonan syndromes in patients with PTPN11 pathogenic variants.,Clinical Genetics

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Overlapping phenotypes between SHORT and Noonan syndromes in patients with PTPN11 pathogenic variants.
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-03-31 , DOI: 10.1111/cge.13746
Emmanuelle Ranza _{1,

2} , Anne Guimier _{1,

3} , Alain Verloes ₄ , Yline Capri ₄ , Charles Marques ₅ , Martine Auclair ₆ , Michèle Mathieu-Dramard ₇ , Gilles Morin ₇ , Julien Thevenon _{8,

9} , Laurence Faivre _{8,

9} , Christel Thauvin-Robinet _{8,

9} , A Micheil Innes ₁₀ , David A Dyment ₁₁ , Corinne Vigouroux _{6,

12} , Jeanne Amiel _{1,

3}

Affiliation

Service de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
Department of Genetics, APHP- Robert Debré University Hospital & INSERM UMR1141, Paris, France.
Faculdade de Medicina, Centro Universitario Estacio, Ribeirao Preto, São Paulo, Brazil.
Centre de Recherche Saint-Antoine, et Institut de Cardiométabolisme et Nutrition (ICAN), Sorbonne Université, INSERM UMR_S 938, Paris, France.
Service de Génétique Clinique, Centre de référence maladies rares, CHU d'Amiens-site Sud, Amiens, France.
Centre de Référence maladies rares « Anomalies du Développement et syndrome malformatifs » de l'Est et Centre de Génétique, FHU TRANSLAD, Hôpital d'Enfants, CHU, Dijon, France.
Equipe d'Accueil 4271, Génétique des Anomalies du Développement, FHU TRANSLAD, Université de Bourgogne, Dijon, France.
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
AP-HP, Hôpital Saint-Antoine, Centre de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service d'Endocrinologie, Diabétologie et Endocrinologie de la Reproduction, and Laboratoire Commun de Biologie et Génétique Moléculaires, Paris, France.

Overlapping syndromes such as Noonan, Cardio‐Facio‐Cutaneous, Noonan syndrome (NS) with multiple lentigines and Costello syndromes are genetically heterogeneous conditions sharing a dysregulation of the RAS/mitogen‐activated protein kinase (MAPK) pathway and are known collectively as the RASopathies. PTPN11 was the first disease‐causing gene identified in NS and remains the more prevalent. We report seven patients from three families presenting heterozygous missense variants in PTPN11 probably responsible for a disease phenotype distinct from the classical Noonan syndrome. The clinical presentation and common features of these seven cases overlap with the SHORT syndrome. The latter is the consequence of PI3K/AKT signaling deregulation with the predominant disease‐causing gene being PIK3R1 . Our data suggest that the phenotypic spectrum associated with pathogenic variants of PTPN11 could be wider than previously described, and this could be due to the dual activity of SHP2 (ie, PTPN11 gene product) on the RAS/MAPK and PI3K/AKT signaling.

中文翻译：

PTPN11病原体变异患者中SHORT和Noonan综合征之间的重叠表型。

重叠综合征（例如Noonan，心-面部-面部，Noonan综合征（NS）伴有多种lentigines和Costello综合征）是遗传异质性疾病，共享RAS /促分裂原活化蛋白激酶（MAPK）通路的失调，被统称为RA病。PTPN11是在NS中鉴定出的第一个致病基因，并且仍然更加流行。我们报告了来自三个家庭的七名患者，他们在PTPN11中出现杂合错义变体，可能与典型的Noonan综合征的疾病表型有关。这七个病例的临床表现和共同特征与SHORT综合征重叠。后者是PI3K / AKT信号失控的结果，其中主要的致病基因为PIK3R1。我们的数据表明，与PTPN11的致病变异相关的表型谱可能比以前描述的更宽，这可能是由于SHP2（即PTPN11基因产物）对RAS / MAPK和PI3K / AKT信号的双重活性。

更新日期：2020-03-31

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