Intellectual disability update Jan 2018

Gene: MTOR

Comment when marking as ready: Sufficient cases, phenotype is appropriate for the ID panel.

Created: 5 Mar 2018, 12:15 p.m.

Comment on mode of pathogenicity: Note: only missense variants have been reported to date. The relevant spectrum of variants may be limited (? consistent with gain of function). The pick up re somatic mosaic variants is likely to be limited (re focal cortical dysplasia phenotype) however if detected, they could be of clinical relevance.

Created: 5 Mar 2018, 12:14 p.m.

Comment on phenotypes: Note: only missense variants have been reported to date. The relevant spectrum of variants may be limited (? consistent with gain of function). I note that the pick up for somatic mosaic variants regarding the focal cortical dysplasia phenotype is likely to be limited, however it has been included as there is sufficient phenotypic overlap with this panel.

Created: 5 Mar 2018, 12:13 p.m.

Green List (high evidence)

Comment on publications: Added PMID: 27159400 from internal clinical review suggestion, identified 3 unrelated children (and one more who was identical twin of one of the others) with a consitutional (aternative allele fraction of ~0.5) MTOR mutation with diffuse megalencephaly, ID and autism (as well as other children in whom mosiac mutations were identified and children with focal cortical dysplasia in whom MTOR mutations were found only in somatic tissue). These children don't have Smith-Kingsmore syndrome, no mention of epilepsy in the paper, and had minimal polymicrogyria so it's conceivable they would have been recruited under ID rather than cortical dysplasia panel.

Created: 5 Mar 2018, 4:15 p.m.

added missense and somatic tags. Clinical team review agree that there is evidence for germline and somatic mosaic variants in this gene in association with ID, it should be rated as Green and to include both phenotypes Focal cortical dysplasia, type II, somatic and Smith-Kingsmore syndrome

Created: 5 Mar 2018, 4:13 p.m.

Comment on publications: added publications to support Smith-Kingsmore syndrome, 616638

Created: 28 Feb 2018, 6:25 p.m.

Comment on list classification: Changed status from Red to Green, there is enough evidence to support variants in MTOR causing Smith-Kingsmore syndrome. This is not to be confused with the other gene-phenotype association to Focal cortical dysplasia, type II, somatic, as we cannot currently report on this (somatic/mosaicism)

Created: 28 Feb 2018, 6:21 p.m.

There are more than three unrelated cases with intellectual disability Baynam et al. (2015) PMID:25851998, Mroske et al., (2015) PMID:26542245, Moller et al. (2016) PMID: 27830187 and more recently Gordo et.el (2017) PMID:28892148

Created: 28 Feb 2018, 6:17 p.m.

This is a confirmed DD gene in Gene2Phenotype for Smith-Kingsmore syndrome

Created: 28 Feb 2018, 6:14 p.m.

Variants of MTOR can result in Focal cortical dysplasia, type II, somatic 607341. However, it is also associated to the autosomal dominant syndrome Smith-Kingsmore syndrome which is characterized by intellectual disability, macrocephaly, seizures, umbilical hernia, and facial dysmorphic features, Smith et al. (2013) DOI: 10.4137/JGE.S12583, Baynam et al. (2015) PMID: 25851998.

Created: 28 Feb 2018, 6:13 p.m.