title: Novel pathogenic variant in the HRAS gene with lethal outcome and a broad phenotypic spectrum among Polish patients with Costello syndrome.
abstract: Costello syndrome (CS) is a rare congenital disorder from the group of RASopathies, characterized by a distinctive facial appearance, failure to thrive, cardiac and skin anomalies, intellectual disability, and a predisposition to neoplasia. CS is associated with germline mutations in the proto-oncogene HRAS, a small GTPase from the Ras family. In this study, a molecular and clinical analysis was carried out in eight Polish patients with the Costello phenotype. A molecular test showed two known heterozygous mutations in the first coding exon of the gene in seven patients: p.G12S (n=4) and p.G12A (n=3), and a novel pathogenic variant p.G60V in one child with an unusually severe, lethal course of the syndrome. In addition, a fatal course of CS was present in one patient with the p.G12A mutation and in another with p.G12S, there was a co-occurrence of Turner syndrome because of the distal Xp deletion. A severe clinical manifestation with a lethal outcome in an individual with p.G60V in HRAS and contrary observations of an attenuated phenotype in CS patients with other mutations at glycine-60 residue may suggest that the nature of the substituted amino acid plays a significant role in the clinical variability observed in some CS cases.
authors.affiliation: aDepartment of Medical Genetics, The Children's Memorial Health Institute bDepartment of Paediatrics, Medical University of Warsaw, Warsaw cDepartment of Medical Genetics, Medical College, Jagiellonian University, Cracov, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Pelc
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Ciara
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Jezela-Stanek
authors.forename: Monika
authors.initials: M
authors.lastname: Kugaudo
authors.forename: Agata
authors.initials: A
authors.lastname: Cieślikowska
authors.forename: Dorota
authors.initials: D
authors.lastname: Jurkiewicz
authors.forename: Magdalena
authors.initials: M
authors.lastname: Janeczko
authors.forename: Krystyna
authors.initials: K
authors.lastname: Chrzanowska
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Krajewska-Walasek
authors.forename: Agata
authors.initials: A
authors.lastname: Skórka
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D056685:Costello Syndrome / Q000175:diagnosis* / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D011044:Poland; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)