A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis.

Pauline Arnaud, Caroline Racine, Nadine Hanna, Julien Thevenon, Jean-Luc Alessandri, Dominique Bonneau, Jill Clayton-Smith, Christine Coubes, Bruno Delobel, Sophie Dupuis-Girod, Laurent Gouya, Sylvie Odent, Virginie Carmignac, Christel Thauvin-Robinet, Carine Le Goff, Guillaume Jondeau, Catherine Boileau, Laurence Faivre

Journal: Human genetics 2020;139(4):461-472

PMID: 31980905

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Abstract

SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.

Address: Laboratory for Vascular Translational Science, INSERM U1148, Centre Hospitalo-Universitaire Xavier Bichat, 75018, Paris, France.; Département de Génétique, Centre Hospitalo-Universitaire Xavier Bichat, 46 Rue Henri Huchard, 75018, Paris, France.; UFR de Médecine, Université de Paris, 75018, Paris, France.; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Hôpital d'Enfants, Centre Hospitalier Universitaire Dijon, 14, Rue Gaffarel, 21079, Dijon Cedex, France.; Laboratory for Vascular Translational Science, INSERM U1148, Centre Hospitalo-Universitaire Xavier Bichat, 75018, Paris, France.; Département de Génétique, Centre Hospitalo-Universitaire Xavier Bichat, 46 Rue Henri Huchard, 75018, Paris, France.; Unité de Génétique Clinique,Pôle Couple Enfant, CHU de Grenoble Site Nord-Hôpital Couple-Enfant, 38043, Grenoble, France.; Service de Réanimation Néonatale, Pole Femme-Mère-Enfant, CH Felix Guyon, CHU de La Réunion, La Réunion, Saint-Denis, France.; Département de Biochimie et Génétique et Unité Mitovasc INSERM 1083, CNRS 6015, CHU Angers, 49933, Angers, France.; Manchester Centre For Genomic Medicine, St Mary's Hospital, Manchester and University Hospitals NHS Foundation Trust Manchester Academic Health Sciences Centre, Manchester, UK.; Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.; Centre de Référence Anomalies du Développement et Syndromes Malformatifs Sud-Languedoc Roussillon, Centre Hospitalier Universitaire Montpellier, Montpellier, France.; Centre de Génétique Chromosomique, GHICL, Hôpital Saint Vincent de Paul, Lille, France.; Centre de Compétences Syndrome de Marfan et Syndromes Apparentés, Hospices Civils de Lyon, Lyon, France.; Centre de Référence Syndrome de Marfan et Pathologies Apparentés, APHP, Hôpital Bichat, Paris, France.; Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'inter-région Ouest, Service de Génétique Clinique, Univ Rennes, CNRS, IGDR (Institut de Génétique et Développement de Rennes)-UMR 6290, Centre Hospitalier Universitaire Rennes, 35203, Rennes, France.; INSERM, U1231, Génétique des Anomalies du Développement, 21079, Dijon, France.; UMR Lipides, Nutrition, Cancer, Université de Bourgogne Franche-Comté, 21000, Dijon, France.; INSERM, U1231, Génétique des Anomalies du Développement, 21079, Dijon, France.; UMR Lipides, Nutrition, Cancer, Université de Bourgogne Franche-Comté, 21000, Dijon, France.; Centre de Référence Déficiences Intellectuelles de Causes Rares, Centre Hospitalier Universitaire Dijon, 21079, Dijon, France.; Laboratory for Vascular Translational Science, INSERM U1148, Centre Hospitalo-Universitaire Xavier Bichat, 75018, Paris, France.; Laboratory for Vascular Translational Science, INSERM U1148, Centre Hospitalo-Universitaire Xavier Bichat, 75018, Paris, France.; Centre de Référence Syndrome de Marfan et Pathologies Apparentés, APHP, Hôpital Bichat, Paris, France.; Laboratory for Vascular Translational Science, INSERM U1148, Centre Hospitalo-Universitaire Xavier Bichat, 75018, Paris, France. [email protected].; Département de Génétique, Centre Hospitalo-Universitaire Xavier Bichat, 46 Rue Henri Huchard, 75018, Paris, France. [email protected].; UFR de Médecine, Université de Paris, 75018, Paris, France. [email protected].; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Hôpital d'Enfants, Centre Hospitalier Universitaire Dijon, 14, Rue Gaffarel, 21079, Dijon Cedex, France. [email protected].; INSERM, U1231, Génétique des Anomalies du Développement, 21079, Dijon, France. [email protected].; UMR Lipides, Nutrition, Cancer, Université de Bourgogne Franche-Comté, 21000, Dijon, France. [email protected].

DOI: 10.1007/s00439-019-02102-9

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MeSH Terms: Adolescent, Adult, Arachnodactyly, Child, Child, Preschool, Craniosynostoses, DNA-Binding Proteins, Female, Humans, Male, Marfan Syndrome, Middle Aged, Mutation, Pathology, Molecular, Proto-Oncogene Proteins