Intellectual disability
Gene: SETD1A

SETD1A (SET domain containing 1A)
EnsemblGeneIds (GRCh38): ENSG00000099381
EnsemblGeneIds (GRCh37): ENSG00000099381
OMIM: 611052, Gene2Phenotype
SETD1A is in 4 panels

5 reviews

Arina Puzriakova (Genomics England Curator)

Removed '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

Created: 2 Nov 2020, 5:03 p.m.
Last Modified: 2 Nov 2020, 5:03 p.m.
Panel version: 3.502

Zerin Hyder (Genomics England)

Green List (high evidence)

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

32346159

Created: 29 Sep 2020, 4:53 p.m.
Last Modified: 29 Sep 2020, 4:53 p.m.
Panel version: 3.360

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

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

Created: 8 Jul 2020, 9:23 a.m.
Last Modified: 8 Jul 2020, 9:23 a.m.
Panel version: 3.1510

David Curtis (UCL)

Green List (high evidence)

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

PMID: 26974950

Created: 5 Feb 2018, 2:56 p.m.

Panel version: 1.655

Louise Daugherty (Genomics England Curator)

Red List (low evidence)

added watchgene tag
Created: 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

Created: 18 Dec 2017, 3:39 p.m.

Panel version: 1.664

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Green

Phenotypes

Neurodevelopmental disorder with speech impairment and dysmorphic facies, 619056
Epilepsy, early-onset, with or without developmental delay, 618832

OMIM

611052

Clinvar variants

Variants in SETD1A

Penetrance

None

Publications

Panels with this gene