A novel HRAS c.466C>T p.(Phe156Leu) variant in two patients with attenuated features of Costello syndrome |
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| Authors: | Suzanna Lindsey-Temple Matt Edwards Verena Rickassel Theresa Nauth Georg Rosenberger |
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| Affiliation: | 1.Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW Australia ;2.School of Women’s and Children’s Health, Faculty of Medicine and Health, UNSW, Sydney, NSW Australia ;3.Paediatrics, School of Medicine, Western Sydney University, Hunter Genetics, Newcastle, NSW Australia ;4.Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany |
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| Abstract: | ![]()
Costello syndrome (CS) is caused by heterozygous HRAS germline mutations. Most patients share the HRAS variant p.Gly12Ser that is associated with a typical, homogeneous phenotype. Rarer pathogenic HRAS variants (e.g., p.Thr56Ile) were identified in individuals with attenuated CS phenotypes. The obvious phenotypical variability reflects different dysfunctional consequences of distinct HRAS variants. We report on two boys with the novel de novo HRAS variant c.466 C > T p.(Phe156Leu). Both had severe feeding difficulties, airway obstruction and developmental delay, which are typical findings in CS. They showed subtle facial and dermatologic features consistent with attenuated CS. They significantly differed in their musculoskeletal, cardiovascular and endocrinologic manifestations underscoring the clinical variability of individuals with identical, in particular rarer pathogenic HRAS variants. Functional studies revealed enhanced effector-binding, increased downstream signaling activation and impaired growth factor-induced signaling dynamics in cells expressing HRASPhe156Leu. Our data further illustrate the molecular and phenotypic variability of CS.Subject terms: Genetics research, Disease genetics |
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