Intellectual disability
Gene: U2AF2

U2AF2 (U2 small nuclear RNA auxiliary factor 2)
EnsemblGeneIds (GRCh38): ENSG00000063244
EnsemblGeneIds (GRCh37): ENSG00000063244
OMIM: 191318, Gene2Phenotype
U2AF2 is in 4 panels

5 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Created: 3 May 2024, 11:55 a.m. | Last Modified: 3 May 2024, 11:55 a.m.

Panel Version: 6.11

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Created: 3 May 2024, 11:55 a.m.
Last Modified: 3 May 2024, 11:55 a.m.
Panel version: 6.11

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: As reviewed by Celia Duff, there is sufficient evidence (>3 unrelated cases) available for the association of this gene with global developmental delay, intellectual disability and epilepsy. Hence, this gene should be promoted to green rating at the next GMS review.
Created: 12 Sep 2023, 6:03 p.m. | Last Modified: 12 Sep 2023, 6:03 p.m.

Panel Version: 5.272

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071

Publications

Created: 12 Sep 2023, 6 p.m.
Last Modified: 12 Sep 2023, 6 p.m.
Panel version: 5.272

Celia Duff-Farrier (North Bristol NHS Trust)

Green List (high evidence)

Literature evidence Ref1-5, identification of affected patients in the diagnostic setting (CVA database, 19:55661148:C>T ) and further accounts in open access databases (ClinVar and LOVD), make this gene suitable for clinical review and upgrading to a green gene status on relevant panels. It is associated with a phenotype encompassing dysmorphism, epilepsy, developmental delay, intellectual disability, and brain malformation Ref1-5. There is a recent publication that proposes an extension of this phenotype to include hypomyelination leukodystrophy Ref6. A loss of function mechanism has been suggested, associated with disruption of RNA recognition motifs required for the function of U2AF2 as a pre-mRNA splicing factor Ref4. At least one recurrent pathogenic variant has been identified by this review U2AF2 c.445C>T p.(Arg149Trp). U2AF2 is constrained for missense in gnomAD Z=4.71.
total variants/patients identified
1) De novo U2AF2 (NM_007279.3:c.445C>T p.(Arg149Trp)) recurrent variant; 1x patient in Hiraide (PubMed: 34112922), 1x patient in Kittock (PubMed: 37092751), 2x patients in Kaplanis (Pubmed: 33057194), 7x patients in the Leiden Open Variation Database (LOVD, https://www.lovd.nl/) 1x patient in house BGL and 4x additional on CVA
2) De novo U2AF2 c.603G>T; 1 patient in Wang 2023 (PubMed: 36747105)
3) De novo U2AF2 c.470C>T p.Pro157Leu) in Kuroda (PubMed: 37134193)
4) 9x additional pathogenic or likely pathogenic variants on LOVD
5) 2x additional likely pathogenic variants on ClinVar
6) We are collaborating with a researcher in the USA with a cohort of 40+ cases.

References
1.       PubMed: 28135719 McRae (2017)-DDD data
2.       PubMed: 31785789 Turner (2019)-DDD data
3.       PubMed: 34112922 Hiraide (2021) de novo U2AF2 c.445C>T p.R149W
4.       PubMed: 36747105 Wang (2023) de novo U2AF2 c.603G>T, p.163_201del
5.       PubMed: 37092751 Kittock (2023) de novo U2AF2 c.445C>T p.R149W
Possible emerging phenotype of hypomyelinating leukodystrophy
6.       PubMed: 37134193 Kuroda (2023)
Created: 30 Aug 2023, 9:45 a.m. | Last Modified: 30 Aug 2023, 9:53 a.m.

Panel Version: 5.268

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
intellectual disability, global developmental delay, dysmorphism, epilepsy, brain malformation, microcephaly, possible emerging phenotype of hypomyelinating leukodystrophy.

Publications

(PMID: 28135719):(PMID: 31785789):(PMID: 34112922):(PMID: 36747105):(PMID: 37092751):(PMID 37134193)

Variants in this GENE are reported as part of current diagnostic practice

Created: 30 Aug 2023, 9:45 a.m.
Last Modified: 30 Aug 2023, 9:53 a.m.
Panel version: 5.268

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Created: 4 Dec 2020, 3:13 p.m. | Last Modified: 4 Dec 2020, 3:13 p.m.

Panel Version: 3.597

Created: 4 Dec 2020, 3:13 p.m.
Last Modified: 4 Dec 2020, 3:13 p.m.
Panel version: 3.597

Zornitza Stark (Australian Genomics)

I don't know

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 10 de novo variants (1 in-frame, 8 missense, 1 synoymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided, hence Amber rating).
Sources: Literature
Created: 4 Nov 2020, 9:35 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Developmental disorders

Publications

33057194

Created: 4 Nov 2020, 9:35 a.m.

Panel version: 3.510

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

NHS GMS
Expert Review Green

Phenotypes

neurodevelopmental disorder, MONDO:0700092
intellectual disability, MONDO:0001071

OMIM

191318

Clinvar variants

Variants in U2AF2

Penetrance

None

Publications

Panels with this gene