Mosaic brain disorders - deep sequencing

Gene: RHEB

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy and cortical dysplasia

Publications

• PMID: 33434304
• 37015817

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Comment on list classification: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 31 May 2023, 10:36 a.m. | Last Modified: 31 May 2023, 10:36 a.m.

Panel Version: 0.116

At least 2 additional cases reported (PMID: 33434304; 37015817) with a spectrum of cortical malformations and brain mosaic RHEB variants. This now meets the diagnostic-grade criteria and therefore this gene should be rated Green.

Created: 31 May 2023, 10:35 a.m. | Last Modified: 31 May 2023, 10:35 a.m.

Panel Version: 0.115

Comment on list classification: Only two unrelated cases have been reported to date (PMID: 29051493). Brain imaging did reveal megalencephaly, dilatation of lateral ventricles and a hypoplastic cerebellum. Two unrelated individuals had seizures. Parental gonadal mosaicism was suspected but not confirmed in one family. Overall, RHEB is a good candidate for this panel but additional cases would help corroborate the association. Therefore setting rating as Amber for now.

Created: 22 Dec 2022, 11:34 a.m. | Last Modified: 22 Dec 2022, 11:34 a.m.

Panel Version: 0.55

Comment on publications: PMID:29051493 (2017) analysed 101 mMTOR-related genes in a large ID patient cohort and 2 independent population cohorts. They report 3 individuals (including 2 siblings) with heterozygous RHEB variants. The siblings carried the c.110 C > T (p.Pro37Leu) variant, and a sporadic individual carried the c.202 T>C (p.Ser68Pro) allele. All 3 individuals had short stature (−2 to −3 SD) and early brain overgrowth with pronounced macrocephaly during childhood (+2.5/+3 SD). They had severe to profound ID with hypotonia, as well as autism spectrum disorder. 2 of 3 individuals were reported to have epilepsy. In a zebrafish model, overexpression of RHEB produced megalencephaly, supporting a hyperactivating effect. This is supported in mice where loss of RHEB activity does not cause an overt neurological phenotype.

Created: 22 Dec 2022, 11:26 a.m. | Last Modified: 22 Dec 2022, 11:26 a.m.

Panel Version: 0.54

Publications

• 29051493
• 33434304
• 37015817

I don't know

This gene is not currently associated with a disease phenotype in OMIM, but checked PMID:29051493 to make sure it is the same gene listed in the publication as on this panel and it is, so added the gene-checked tag

Created: 16 Oct 2023, 8:28 p.m. | Last Modified: 16 Oct 2023, 8:28 p.m.

Panel Version: 0.139

The rating of this gene has been updated to Amber and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 5:26 p.m. | Last Modified: 1 Feb 2023, 5:37 p.m.

Panel Version: 0.93

Review submitted on behalf of Dr Lara Menzies, Dr Wendy Jones, Dr Amy McTague. Mode of inheritance: mosaic. Publications: Lee et al 2021 Annals Translational and Clinical Neurology. Mechanism: GOF (MTOR pathway). Penetrance: no information provided.

Created: 21 Dec 2022, 12:16 p.m. | Last Modified: 21 Dec 2022, 12:16 p.m.

Panel Version: 0.2

Phenotypes
Epilepsy and cortical dysplasia

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments