Intellectual disability - microarray and sequencing
Gene: ATP1A3The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 14 Mar 2022, 2:22 p.m. | Last Modified: 14 Mar 2022, 2:22 p.m.
Panel Version: 3.1519
Gene was reassessed following a further Green review by Zornitza Stark (8 Jul 2021). Vetro et al. (PMID: 33880529) identified several individuals with variants in this gene who presented with DD/ID as the predominant feature. Therefore, ATP1A3 will be flagged for GMS expert review as inclusion on this panel may be of value in some patients but previous comments regarding association with several phenotypes should be considered.Created: 20 Sep 2021, 1:25 p.m. | Last Modified: 20 Sep 2021, 1:25 p.m.
Panel Version: 3.1282
Comment on list classification: Maintaining Amber rating on this panel, in line with the previous comments by Louise Daugherty (Genomics England) and internal clinical review.
Heterozygous variants are associated with several phenotypes, not all of which include cognitive impairment. Gain from inclusion on the ID panel is likely smaller than the risk of incidental information for the majority of the ID cohort. Patients are expected to be tested under the paroxysmal central nervous system disorders or dystonia GMS panels.Created: 25 Jan 2021, 10:40 a.m. | Last Modified: 25 Jan 2021, 10:40 a.m.
Panel Version: 3.729
Comment on list classification: Changed from Green to Amber after external clinical comment and internal clinical review. Of the three phenotypes in OMIM that are associated: CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) / Alternating hemiplegia of childhood / Dystonia 12, intellectual disability is only a reported feature in Alternating hemiplegia of childhood. However, all three phenotypes are caused by monoallelic variants and therefore through tiering they will not be readily distinguishable. The other phenotypes include a later onset neurological decline. Overall it was recommended the gene is downgraded to Amber, as although there is ID reported, there is no precedent for presentation with global developmental delay alone. Therefore we would expect this phenotype to be picked up via the brain channelopathy panel (relevant to intermittent / alternating hemiplegia) or the dystonia panel in view of the dystonic component. The gain from inclusion on the ID panel is probably smaller than the risk of incidental information for the majority of the ID cohort.Created: 8 Aug 2018, 12:21 p.m.
Comment on phenotypes: Removed RAPID-ONSET DYSTONIA-PARKINSONISM, as it is only the Alternating Hemiplegia of Childhood (AHC) disorder that includes an ID phenotypeCreated: 8 Aug 2018, 12:09 p.m.
Comment on publications: added publications to support evidence for Alternating hemiplegia of childhood 2 (that includes ID)Created: 1 Aug 2018, 1:54 p.m.
Due to a Amber external review from external reviewer, and looking at the info again in the literature I am not sure why this gene was rated as Green based on the evidence for Dystonia-12, since it seems Alternating hemiplegia of childhood phenotype that includes intellectual disability that is relevant to this panelCreated: 1 Aug 2018, 1:35 p.m.
Sixteen individuals reported with DD/EE.Created: 8 Jul 2021, 8:47 a.m. | Last Modified: 8 Jul 2021, 8:47 a.m.
Panel Version: 3.1163
Four additional individuals with dystonia, dysmorphism, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia, and neonatal onset. All had de novo missense variants. All are described to have global developmental delay, hence supporting upgrade in rating on this panel.Created: 8 Sep 2020, 10:59 p.m. | Last Modified: 8 Sep 2020, 10:59 p.m.
Panel Version: 3.295
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Developmental and epileptic encephalopathy
Publications
Variants in this GENE are reported as part of current diagnostic practice
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
RAPID-ONSET DYSTONIA-PARKINSONISM
Publications
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_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_movement_disorder_list . Main mutation mechanism : All missense/in frameCreated: 27 Jul 2017, 5:08 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; manju_list; GEL_ID_green_20160217; neuro_20160418_strict; All missense/in frame. 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, 12:02 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Mode of pathogenicity
Other
Tag Q3_21_expert_review was removed from gene: ATP1A3.
Source Expert Review Green was added to ATP1A3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Publications for gene: ATP1A3 were set to 22842232; 29396171; 29291920; 22842232; 28969699; 32802951
Tag Q3_21_expert_review tag was added to gene: ATP1A3.
Publications for gene: ATP1A3 were set to 22842232; 29396171; 29291920; 22842232; 28969699
Gene: atp1a3 has been classified as Amber List (Moderate Evidence).
Gene: atp1a3 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: ATP1A3 were set to Alternating Hemiplegia of Childhood (AHC), intellectual disability
Publications for gene: ATP1A3 were set to 22842232; 29396171; 29291920; 22842232; 28969699
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.
This gene has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
ATP1A3 was added to Intellectual disabilitypanel. Sources: Expert Review Amber
ATP1A3 was created by ellenmcdonagh