Intellectual disability - microarray and sequencing
Gene: SETD1ARemoved 'watchlist' and added 'for-review' tag as there is now sufficient evidence to rate this gene Green at the next GMS panel update.Created: 2 Nov 2020, 5:03 p.m. | Last Modified: 2 Nov 2020, 5:03 p.m.
Panel Version: 3.502
Recent publication by Kummeling et al defines the clinical features associated with haploinsufficiency of SETD1A. Described 15 individuals with de novo SETD1A variants presenting with global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. Examined cellular phenotypes in three patient-derived cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp and results suggested that that these variants behave as loss-of-function (LoF) alleles.Created: 29 Sep 2020, 4:53 p.m. | Last Modified: 29 Sep 2020, 4:53 p.m.
Panel Version: 3.360
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Epilepsy, early-onset, with or without developmental delay; craniofacial dysmorphisms; behavioural/psychiatric abnormalities
Publications
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
There is enough evidence for this gene to be rated GREEN at the next major review.
Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for intellectual disability. At least 4 variants reported, 3 de novo and 1 found segregating in a family.Created: 8 Jul 2020, 9:23 a.m. | Last Modified: 8 Jul 2020, 9:23 a.m.
Panel Version: 3.157
Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. https://www.nature.com/articles/nn.4267
PMID: 26974950
LOF variants were seen only in subjects with schizophrenia without marked physical abnormalities and in subjects described as having developmental delay within a sample of children with diverse, severe developmental disorders. A further subject had mental retardation, short stature, mild facial dysmorphology and EEG abnormalities and was also diagnosed with delusional disorder and unspecified psychosis at 15 years of age. An additional subject had epilepsy and personality disorder.
Thus it seems that LOF variants in SETD1A can produce developmental disorder with intellectual disability as part of the phenotype or can result in other neuropsychiatric diagnoses including schizophrenia without severe intellectual disability.Created: 5 Feb 2018, 2:56 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Schizophrenia; developmental disorder
Publications
added watchgene tagCreated: 26 Feb 2018, 4:36 p.m.
Comment on list classification: Changed status from Red to Amber after internal clinical review.
An external reviewer suggested a Green rating, however during internal review there was some concern rating the gene Green in the ID panel in view of the presence (albeit small numbers; 2) in ExAC, and it is unclear if the initial presentation was with Schizophrenia in the majority. So the level of ID may not be great enough from the reported cases to date to warrant inclusion, however it was noted that LoF variants were found in 4 cases from an ID cohort, so the Amber rating was suggested until further reports.Created: 26 Feb 2018, 4:27 p.m.
Probable gene in Developmental Disorders Genotype-Phenotype Database (DDG2P) with the attributed disease intellectual disability PMID:28135719. Singh et al (2016) PMID: 26974950 analyzed whole genome sequences of 4,264 schizophrenia cases and identified rare loss of function variants in SETD1A and risk of schizophrenia and other neurodevelopmental phenotypes, one being intellectual disability. There were four patients noted with schizophrenia and delayed developmental milestones, however it was noted that the study design focused on schizophrenia and not ID, so could not confirm that the variants were specifically associated with the cognitive features.Created: 18 Dec 2017, 3:39 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Intellectual disability
Publications
Tag for-review was removed from gene: SETD1A.
Source Expert Review Green was added to SETD1A. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Phenotypes for gene: SETD1A were changed from Schizophrenia; developmental disorder; Intellectual disability to Neurodevelopmental disorder with speech impairment and dysmorphic facies, 619056; Epilepsy, early-onset, with or without developmental delay, 618832
Publications for gene: SETD1A were set to 28135719; 26974950; 31197650
Tag watchlist was removed from gene: SETD1A.
Tag for-review tag was added to gene: SETD1A.
Publications for gene: SETD1A were set to 28135719; 26974950
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.
Phenotypes for SETD1A were set to Schizophrenia; developmental disorder; Intellectual disability
This gene has been classified as Amber List (Moderate Evidence).
This gene has been classified as Amber List (Moderate Evidence).
SETD1A was added to Intellectual disability panel. Sources: Expert Review Red
SETD1A was created by Ellen McDonagh