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.
Costello syndrome
HRAS
HRAS-related RASopathy
RASopathy
attenuated phenotype
loose anagen hair
p.Ala59Gly
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
revised:
26
04
2023
received:
25
01
2023
accepted:
29
04
2023
medline:
19
7
2023
pubmed:
17
5
2023
entrez:
17
5
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37194190
doi: 10.1002/ajmg.a.63240
doi:
Substances chimiques
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
HRAS protein, human
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2074-2082Informations de copyright
© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
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