Truncating Variants in <scp><i>RREB1</i></scp> Cause a Novel <scp>RASopathy</scp> Syndrome of Congenital Heart Disease, Genitourinary Malformations, and Developmental Delay
The interstitial 6p microdeletion syndrome is characterized by dysmorphic facies and structural heart, kidney, brain, and musculoskeletal differences. RREB1 haploinsufficiency and consequent abnormal RAS-MAPK pathway signaling have been proposed as a driver of the disease phenotype; however, apart from a single case report, the phenotype of intragenic RREB1 variants is unknown. Here we present a cohort of 6 individuals with truncating RREB1 variants. Phenotypes include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Our data support RREB1 as a currently under-recognized cause of a RASopathy phenotype with features that overlap with Noonan, Costello, and Cardiofaciocutaneous syndromes.
Authors
- Karen Stals (ORCID: https://orcid.org/0000-0002-3255-7044)
- Alisa Gaskell
- Michel Guipponi
- Christophe Philippe (ORCID: https://orcid.org/0000-0001-7098-6520)
- Kiersten N Keller
- Alanna Strong (ORCID: https://orcid.org/0000-0001-9261-244X)
- Paul B. Vrana
- A. Micheil Innes (ORCID: https://orcid.org/0000-0001-9881-5467)
- Antonio Vitobello (ORCID: https://orcid.org/0000-0003-3717-8374)
- Alyssa L. Rippert (ORCID: https://orcid.org/0000-0003-4735-5223)
- Claudine Rieubland
- Bimal P. Chaudhari (ORCID: https://orcid.org/0000-0002-0115-949X)
- Caoimhe McKenna (ORCID: https://orcid.org/0000-0003-1763-4889)
- Rebecca C. Ahrens‐Nicklas (ORCID: https://orcid.org/0000-0001-8243-7123)
- Elizabeth Bhoj (ORCID: https://orcid.org/0000-0001-5748-3507)
- Mathilde Renaud
- Brandon S. Stone
Institutions
- University of Geneva (CH)
- Belfast Health and Social Care Trust (GB)
- Nationwide Children's Hospital (US)
- Children's Hospital of Philadelphia (US)
- Inserm (FR)
- University of Calgary (CA)
- University of Exeter (GB)
- Alberta Children's Hospital (CA)
- Children's Hospital Colorado (US)
- Hôpital d'Enfants (FR)
- University Hospital of Geneva (CH)
- CHU Dijon Bourgogne (FR)
- Centre Hospitalier Régional de Metz-Thionville (FR)
- Centre de recherche Translationnelle en Médecine moléculaire (FR)
- Genomics (United Kingdom) (GB)
- Nutrition-Génétique et Exposition aux Risques Environnementaux (FR)
- Laboratoire de Génétique Médicale (FR)
- The Ohio State University (US)
- University of Pennsylvania (US)
- Université de Lorraine (FR)
- University of Colorado Denver (US)
Publication Details
- Journal
- American Journal of Medical Genetics Part A
- Published
- 2025-05-26
- DOI
- https://doi.org/10.1002/ajmg.a.64119
- Citations
- 3
- Primary Topic
- Protein Tyrosine Phosphatases
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Institutes of Health