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Case Reports
. 2025 Oct;197(10):e64119.
doi: 10.1002/ajmg.a.64119. Epub 2025 May 26.

Truncating Variants in RREB1 Cause a Novel RASopathy Syndrome of Congenital Heart Disease, Genitourinary Malformations, and Developmental Delay

Alanna Strong  1   2   3 , Caoimhe McKenna  4 , Karen Stals  5 , Antonio Vitobello  6   7 , Mathilde Renaud  8   9   10 , Claudine Rieubland  11 , Michel Guipponi  11   12 , Christophe Philippe  13 , Paul Vrana  14 , Alisa Gaskell  14   15 , A Micheil Innes  16   17   18 , Alyssa L Rippert  1   19 , Rebecca Ahrens-Nicklas  1   3 , Elizabeth Bhoj  1   3 , Kiersten Keller  1 , Bimal P Chaudhari  20   21   22 , Brandon S Stone  21   23
Affiliations
Case Reports

Truncating Variants in RREB1 Cause a Novel RASopathy Syndrome of Congenital Heart Disease, Genitourinary Malformations, and Developmental Delay

Alanna Strong et al. Am J Med Genet A. 2025 Oct.

Abstract

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.

Keywords: RREB1; Noonan syndrome; RAS/MAPK; RASopathy.

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References

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