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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The mechanistic target of rapamycin (mTOR) pathway is implicated in focal epilepsies and cortical malformations, termed mTORpathies.
• Ras homolog enriched in brain (RHEB) is a key activator of mTOR complex 1 (mTORC1).
• Somatic RHEB variants are linked to focal cortical dysplasia and hemimegalencephaly, but germline variants are less understood in neurodevelopmental disorders.

Purpose of the Study:

• To investigate the role of germline RHEB variants in neurodevelopmental disorders.
• To characterize the phenotype associated with a novel germline RHEB variant.
• To expand the known genotype and phenotype spectrum of RHEB-related mTORpathies.

Main Methods:

• Clinical case description of a patient with global developmental delay and epilepsy.
• Identification and characterization of a novel germline de novo heterozygous missense variant in the RHEB gene (c.71T>C; p.Ile24Thr).
• Literature review and comparison with previously reported patients with RHEB variants.

Main Results:

• A patient with global developmental delay and epilepsy was found to carry a novel germline de novo heterozygous missense variant in RHEB.
• This variant expands the spectrum of RHEB mutations associated with mTORpathies.
• The study contributes to a broader understanding of RHEB's role in neurodevelopmental disorders.

Conclusions:

• Germline RHEB variants can cause neurodevelopmental disorders including epilepsy and global developmental delay.
• This case highlights the importance of considering RHEB in the genetic etiology of mTORpathies.
• Further research is warranted to fully elucidate the spectrum of RHEB-associated neurodevelopmental phenotypes.