Header

UZH-Logo

Maintenance Infos

A very mild phenotype in six individuals of a three-generation family with the novel HRAS variant c.176C > G p.(Ala59Gly): Emergence of a new HRAS-related RASopathy distinct from Costello syndrome


Frey, Tanja; Ivanovski, Ivan; Bahr, Angela; Zweier, Markus; Laube, Julia; Luchsinger, Isabelle; Steindl, Katharina; Rauch, Anita (2023). A very mild phenotype in six individuals of a three-generation family with the novel HRAS variant c.176C > G p.(Ala59Gly): Emergence of a new HRAS-related RASopathy distinct from Costello syndrome. American Journal of Medical Genetics. Part A, 191(8):2074-2082.

Abstract

Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in HRAS. The vast majority of affected patients share recurring variants affecting HRAS codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the HRAS variant c.176C>T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome-like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS-related RASopathy for patients carrying HRAS variants affecting codons 58, 59, 60.

Abstract

Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in HRAS. The vast majority of affected patients share recurring variants affecting HRAS codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the HRAS variant c.176C>T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome-like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS-related RASopathy for patients carrying HRAS variants affecting codons 58, 59, 60.

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Downloads

52 downloads since deposited on 23 May 2023
52 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
08 Research Priority Programs > Adaptive Brain Circuits in Development and Learning (AdaBD)
04 Faculty of Medicine > University Children's Hospital Zurich > Clinic for Surgery
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Genetics (clinical), attenuated phenotype, Costello syndrome, HRAS, HRAS-related RASopathy, loose anagen hair, p.Ala59Gly, RASopathy
Language:English
Date:August 2023
Deposited On:23 May 2023 07:29
Last Modified:29 Apr 2024 01:37
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1552-4825
Additional Information:DATA AVAILABILITY STATEMENT Data sharing is not applicable to this article as no new data were created or analyzed in this study. The familial HRAS variant was submitted to ClinVar (SCV002818457, held until published).
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/ajmg.a.63240
Related URLs:https://doi.org/10.1002/ajmg.a.63357
PubMed ID:37194190
Project Information:
  • : FunderUniversity of Zurich (UZH)
  • : Grant IDURPP ITINERARE
  • : Project TitleUniversity Research Priority Program ITINERARE: Innovative Therapies inRare Diseases, Zurich, Switzerland
  • : Project Websitehttps://www.itinerare.uzh.ch/en.html
  • : FunderUniversity of Zurich (UZH)
  • : Grant IDURPP AdaBD
  • : Project TitleUniversity Research Priority Program AdaBD: Adaptive Brain Circuits in Development and Learning,
  • : Project Websitehttps://www.adabd.uzh.ch/en.html
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)