RASopathies

Gene: RREB1

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (seven unrelated patients) in support of the disease association. Hence, this gene has been promoted to green rating on this panel.

Created: 10 Oct 2025, 2:22 p.m. | Last Modified: 10 Oct 2025, 2:22 p.m.

Panel Version: 1.86

PMID:38332451 (2024) reported the first patient with RREB1-associated Noonan-like RASopathy. A pathogenic de novo variant in RREB1 gene was identified by whole-genome sequencing and was confirmed by Sanger sequencing in the proband (c.2677del/ p.Ala893Argfs*20). The patient presented with severe intellectual disability, delayed motor skills, short stature, short neck, and distinctive facial dysmorphisms.

PMID:40418122 (2025) reported a cohort of six individuals with a RASopathy phenotype, which include mild dysmorphisms, congenital heart disease, genitourinary malformations, dental anomalies, and developmental delay. Global developmental delay was reported in two of these six patients. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants).

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

Created: 10 Oct 2025, 2:20 p.m. | Last Modified: 10 Oct 2025, 2:20 p.m.

Panel Version: 1.83

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
RASopathy, MONDO:0021060

Publications

• 38332451
• 40418122

Green List (high evidence)

6 additional individuals with truncating variants in RREB1 gene and a Rasopathy phenotype, features including congenital heart disease, developmental delay, short stature, and dysmorphic facial features (PMID: 40418122). RREB1 encodes a transcriptional repressor of Ras-MAPK signalling. Supporting functional evidence and animal models.

Created: 30 Jul 2025, 11:53 a.m. | Last Modified: 30 Jul 2025, 11:53 a.m.

Panel Version: 1.83

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Rasopathy; Noonan-like; developmental disorder

Publications

• PMID: 40418122

Comment on list classification: Rating Red as currently only a single individuals reported (PMID:32938917) with clinical features consistent with a Noonan-spectrum disorder and a 6p-interstitial microdeletion which encompassed 11 genes, including RREB1. Additional cases would help delineate the relevance of the RREB1 gene to the observed phenotype.

Created: 7 Oct 2020, 2:48 p.m. | Last Modified: 7 Oct 2020, 2:48 p.m.

Panel Version: 1.62

Red List (low evidence)

Single individual reported with Noonan syndrome-like features and a deletion encompassing RREB1. Overlapping deletions in publicly reported databases examined, and RREB1 postulated to be the key gene. Rreb1 hemizygous mice display orbital hypertelorism and age dependent cardiac hypertrophy. RREB1 recruits SIN3A and KDM1A to an RRE in target promoters in human and murine cells to control histone H3K4 methylation of MAPK pathway genes. In summary, single well phenotyped individual with a CNV and experimental data to support gene-disease association.
Sources: Literature

Created: 5 Oct 2020, 8:13 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Noonan syndrome-like disorder

Publications

• 32938917