Fetal anomalies
Gene: SETD2
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 4:26 p.m. | Last Modified: 30 Jan 2023, 4:26 p.m.
Panel Version: 2.10
Comment on list classification: Following clinical review, it was agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update.Created: 6 Sep 2022, 2:51 p.m. | Last Modified: 6 Sep 2022, 2:51 p.m.
Panel Version: 1.968
This gene and phenotype were reviewed during a meeting on 21st July 2022 between representatives of the North Thames and Central & South R21 testing GLHs.
Clinical review and curation was performed by Lyn Chitty, Alison Male, Rhiannon Mellis (North Thames GLH), and Stephanie Allen, Denise Williams, Esther Kinning and Anna de Burca (Central & South GLH).
Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.
Details of review:
We have previously reviewed this gene at meetings in October 2020 and October 2021 and decided not to suggest upgrade on the FA panel at that time because the phenotype (Luscan-Lumish syndrome) was felt to be predominantly postnatal overgrowth and behavioural issues/intellectual disability/autism spectrum disorders, which would not be detectable on prenatal imaging.
However, at this review it was noted that Rabin et al (PMID: 32710489) report a distinct sub-group of patients with de novo variants in codon 1740 of SETD2 whose features differ, and which may present with a prenatal phenotype (microcephaly, structural brain anomalies, multicystic dysplastic kidneys). The authors suggest this may be due to another mechanism such as gain of function rather than the ususal loss of function recognised in Luscan-Lumish syndrome.
Also note one fetal case in Qi et al 2020 (PMID: 33255631) with "Ventriculomegaly, cerebellar medulla pool widened, separated cerebellar hemisphere, Ventricular septal defect, renal pelvis broadening" but the variant in this case was c.5086C>T (p.R1696W), not codon 1740.Created: 2 Sep 2022, 4:16 p.m. | Last Modified: 2 Sep 2022, 4:16 p.m.
Panel Version: 1.964
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
microcephaly; profound intellectual disability; congenital anomalies; dysmorphic facial features
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
DDG2P rating in original PAGE list: Probable for SETD2-associated Overgrowth SyndromeCreated: 11 Dec 2018, 9:05 a.m.
Tag Q3_22_rating was removed from gene: SETD2. Tag Q3_22_NHS_review was removed from gene: SETD2.
Source Expert Review Green was added to SETD2. Source NHS GMS was added to SETD2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: setd2 has been classified as Amber List (Moderate Evidence).
Mode of pathogenicity for gene: SETD2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Phenotypes for gene: SETD2 were changed from SETD2-associated Overgrowth Syndrome to microcephaly; profound intellectual disability; congenital anomalies; dysmorphic facial features
Publications for gene: SETD2 were set to
Tag Q3_22_rating tag was added to gene: SETD2. Tag Q3_22_NHS_review tag was added to gene: SETD2.
gene: SETD2 was added gene: SETD2 was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber Mode of inheritance for gene: SETD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: SETD2 were set to SETD2-associated Overgrowth Syndrome