Intellectual disability - microarray and sequencing
Gene: MTORComment 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.
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 syndromeCreated: 5 Mar 2018, 4:13 p.m.
Comment on publications: added publications to support Smith-Kingsmore syndrome, 616638Created: 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:28892148Created: 28 Feb 2018, 6:17 p.m.
This is a confirmed DD gene in Gene2Phenotype for Smith-Kingsmore syndromeCreated: 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.
Comment on list classification: De novo somatic variants in this gene have been reported in brain tissue of patients with seizures due to focal cortical dysplasia type 2 in more than 6 patients (PMID: 26018084;27830187;25878179). PMID:27830187 also reports an inherited variant identified in a mother-daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy. Functional in vitro studies in PMID: 26018084 indicate that the mechanism of action may be activating somatic mutations.Created: 22 Sep 2017, 1:37 p.m.
This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_2_4_2017;in_manual . Main mutation mechanism : All missense/in frameCreated: 27 Jul 2017, 7:42 p.m.
This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation TrustCreated: 19 Jul 2017, 12:53 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Mode of pathogenicity
Other
Mechanism: MosaicCreated: 16 Nov 2015, 11:41 a.m.
Mode of inheritance
Other - please specify in evaluation comments
Phenotypes
HEMIMEGALENCEPHALY MTOR
Publications
Publications for gene: MTOR were set to 26542245; 27830187; 25851998; 28892148; DOI: 10.4137/JGE.S12583; 27159400
Source Victorian Clinical Genetics Services was added to MTOR.
This gene has been classified as Green List (High Evidence).
MTOR Source: Expert Review Green was removed from gene: MTOR
MTOR Source: Expert Review Amber was removed from gene: MTOR
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Expert Review Green was added to MTOR. Panel: Intellectual disability Publications for gene MTOR was set to ['26542245', '27830187', '25851998', '28892148', 'DOI: 10.4137/JGE.S12583', '27159400']
Mode of pathogenicity for MTOR was changed to Other - please provide details in the comments
Phenotypes for MTOR were set to Focal cortical dysplasia, type II, somatic 607341
Publications for MTOR were set to 23934111; 25529582; 26018084; 27830187; 25878179
Mode of inheritance for MTOR was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
This gene has been classified as Amber List (Moderate Evidence).
Publications for MTOR were set to 23934111;25529582;
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
MTOR was created by ellenmcdonagh
MTOR was added to Intellectual disabilitypanel. Sources: Expert Review Red