Monogenic short stature

Gene: RREB1

Red List (low evidence)

Comment on list classification: The eligibility criteria for R453 in the National Genomic Test Directory specifies that the patients should have the height at <-3 SD below mean for the age to be included on this panel. As the reported patients do not meet this criteria, this gene has been rated red with the current evidence.

This gene has already been proposed for green rating on R29 Intellectual disability panel and hence will feed into R27 Paediatric disorders.

Created: 5 Aug 2025, 7:39 p.m. | Last Modified: 5 Aug 2025, 7:39 p.m.

Panel Version: 1.22

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. The height and weight of the patient was <3 centile at 3.25 years of age.

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. They were identified with six different truncating RREB1 variants via exome sequencing (five patients with de novo and one patient with paternally inherited variants). Only one of the six reported patients had the height of ~-2SD below mean for the age.

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

Created: 5 Aug 2025, 7:29 p.m. | Last Modified: 5 Aug 2025, 7:33 p.m.

Panel Version: 1.19

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.
Sources: Literature

Created: 30 Jul 2025, 11:54 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Rasopathy; Noonan-like; developmental disorder

Publications

• PMID: 40418122