A Novel RHEB Germline Variant Associated With Intellectual Disability and Epilepsy: Expanding the Spectrum of mTORopathies

• Published in: Clinical genetics Vol. 108; no. 2; pp. 218 - 223
• Main Authors: Trujillo‐Quintero, Juan Pablo, Brunet‐Vega, Anna, Spataro, Nino, Petanas, Joan, Gallego, Oriol, Mateo, Francesca, Pujana, Miquel Angel, Ruiz, Anna
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2025
• Subjects: Dysplasia; Epilepsy; Epilepsy - genetics; Epilepsy - pathology; Genetic diversity; Genetic Predisposition to Disease; Genotypes; Germ-Line Mutation - genetics; Humans; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - pathology; mTOR; mTORopathies; Mutation, Missense; neurodevelopmental disorder; Neurodevelopmental disorders; Phenotype; Phenotypes; Rapamycin; Ras Homolog Enriched in Brain Protein - genetics; RHEB; TOR protein; TOR Serine-Threonine Kinases - genetics; epilepsy; mTOR; mTORopathies; RHEB; neurodevelopmental disorder
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.14734

ABSTRACT The mTOR cascade is a critical player in the pathogenesis of focal epilepsies and cortical malformations, collectively referred to as mTORopathies. The Ras homolog enriched in brain (RHEB) gene is a member of the RAS‐family GTPases and a potent activator of the mechanistic target of rapamycin complex (mTORC1). Brain somatic variants in the RHEB gene have been described in patients affected by focal cortical dysplasia and hemimegalencephaly abnormalities. Conversely, germline genetic variants in the RHEB gene have been poorly reported in patients with neurodevelopmental disorders. This study describes the phenotype of a patient with global developmental delay and epilepsy carrying a novel germline de novo heterozygous missense variant (c.71 T>C; p.Ile24Thr) in the RHEB gene. Previously reported patients are reviewed and compared to the case reported here, expanding the genotype and phenotype spectrum of mTORopathies. The mTOR cascade is a critical player in the pathogenesis of focal epilepsies and cortical malformations, collectively referred to as mTORopathies. We report a novel germline de novo heterozygous missense variant (c.71 T>C; p.Ile24Thr) in the RHEB gene. Only a few patients have been reported in the literature, and phenotypic features include intellectual disability, epilepsy, and behavioral abnormalities.