Cerebral vascular malformations

Gene: CHD4

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, 10:21 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, 12:56 p.m. | Last Modified: 6 Oct 2022, 12:56 p.m.

Panel Version: 2.60

I don't know

Comment on phenotypes: Moyamoya disease MONDO:0016820 is not specific to CHD4 variants.

Created: 11 Oct 2022, 11:53 a.m. | Last Modified: 11 Oct 2022, 11:53 a.m.

Panel Version: 2.63

Q2_21_expert_review tag added in order to ask whether the evaluation working group would like to seek specialist opinion on this gene / disease association.

Created: 24 Jun 2021, 3:23 p.m. | Last Modified: 24 Jun 2021, 3:24 p.m.

Panel Version: 2.51

Comment on list classification: After consultation with Helen Brittain (Clinical Fellow, Genomics England), CHD4 has been given an amber rating, as the clinical features of the cases reported may not be relevant to this panel. PMID 31474762 reports a single de novo missense variant in a case of Moyamoya angiopathy, six further CHD4 variants were also identified in this study, however, the pattern of inheritance was uncertain. PMID 27616479 found a CHD4 missense variant in a case who also had Moyama angiopathy and two further de novo missense variants were reported in probands with congenital heart disease who had neurodevelopmental deficit (PMID 28991257).

Created: 28 Apr 2021, 2:49 p.m. | Last Modified: 11 Oct 2022, 1:39 p.m.

Panel Version: 2.63

Red List (low evidence)

5 individuals reported with Moya Moya and ID, but only in one was de novo inheritance confirmed. 4 missense variants and one canonical splice.
Sources: Literature

Created: 9 Dec 2020, 7:09 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Moya Moya; Sifrim-Hitz-Weiss syndrome, MIM# 617159

Publications

• 31474762