Fetal anomalies
Gene: SETD2

SETD2 (SET domain containing 2)
EnsemblGeneIds (GRCh38): ENSG00000181555
EnsemblGeneIds (GRCh37): ENSG00000181555
OMIM: 612778, Gene2Phenotype
SETD2 is in 5 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

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

Created: 6 Sep 2022, 2:51 p.m.
Last Modified: 6 Sep 2022, 2:51 p.m.
Panel version: 2.10

Rhiannon Mellis (Great Ormond Street Hospital)

Green List (high evidence)

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

PMID: 32710489
33255631

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Created: 2 Sep 2022, 4:16 p.m.
Last Modified: 2 Sep 2022, 4:16 p.m.
Panel version: 1.964

Rebecca Foulger (Genomics England curator)

I don't know

DDG2P rating in original PAGE list: Probable for SETD2-associated Overgrowth Syndrome
Created: 11 Dec 2018, 9:05 a.m.

Created: 11 Dec 2018, 9:05 a.m.

Panel version: 0.9

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

NHS GMS
Expert Review Green
PAGE DD-Gene2Phenotype

Phenotypes

microcephaly
profound intellectual disability
congenital anomalies
dysmorphic facial features

OMIM

612778

Clinvar variants

Variants in SETD2

Penetrance

None

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

Panels with this gene