Cerebral vascular malformations

Gene: SETD5

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber.

Additional comments from reviewing GLHs: E: I can not find any new published evidence that this gene is associated with Cerebral vascular phenotype since 2020 publication - PMID 31474762 and Helens review in PanelApp. Large cohort study of Moyamoya angiopathy does not identify any individuals with variants in these genes - PMID:37012328. NW: Not enough evidence - limited to one paper only. NEY: moyamoya (the association) seems to be a small part of a developmental disorder phenotype and not a key feature in patients with variants in these genes. They feel more like R27 developmental disorder genes to me. I would keep them as amber. All of the moyamoya diagnoses we have had so far have been in RNF213, which is a pure moyamoya gene.

Created: 6 Dec 2024, 10:20 a.m. | Last Modified: 6 Dec 2024, 10:22 a.m.

Panel Version: 3.18

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before promoting this gene to green.

Created: 30 Jan 2023, 4:01 p.m. | Last Modified: 30 Jan 2023, 4:01 p.m.

Panel Version: 2.68

Updating tags to be Q3_22_expert_review and Q3_22_rating so that gene is included in the next GMS report (Oct 2022)

Created: 6 Oct 2022, 12:58 p.m. | Last Modified: 6 Oct 2022, 12:58 p.m.

Panel Version: 2.60

I don't know

After consultation with Helen Brittain (Clinical Fellow, Genomics England), SETD5 has been given an amber rating. SETD5 variants were reported in PMID: 24680889, 2302093, 25138099 & 31474762, but there was insufficient clinical data to classify the cases reported as having features of Moyamoya disease.

Created: 11 Oct 2022, 12:37 p.m. | Last Modified: 11 Oct 2022, 1:34 p.m.

Panel Version: 2.63

Comment on phenotypes: Moyamoya disease MONDO:0016820 is not specific to SETD5 variants.

Created: 11 Oct 2022, 11:52 a.m. | Last Modified: 11 Oct 2022, 11:52 a.m.

Panel Version: 2.61

Comment on list classification: Associated with Mental retardation, autosomal dominant 23 OMIM:615761 in OMIM and as confirmed Gen2Phen gene. At least one de novo variant has been reported a case of Moyamoya disease MONDO:0016820, who also had features of OMIM:615761, two further variants were found, but it was not possible to report their inheritance (PMID 31474762). Eight de novo SETD5 variants have been reported in Mental retardation, autosomal dominant 23 OMIM:615761 (PMIDs 24680889, 23020937, 25138099). However, none of these reported detailed neurological examinations that could have diagnosed Moyamoya disease.

Created: 28 Apr 2021, 4:45 p.m. | Last Modified: 29 Jun 2021, 10:52 a.m.

Panel Version: 2.52

Red List (low evidence)

Single family reported with de novo SETD5 frameshift in a child with ID and Moya Moya. 2 other families with novel missense and concordant phenotypes but no parental segregation performed.
Sources: Literature

Created: 9 Dec 2020, 7:08 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Moya Moya; Mental retardation, autosomal dominant 23, MIM# 615761

Publications

• 31474762