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DDG2P

Gene: AFF2

Green List (high evidence)
AFF2 (AF4/FMR2 family member 2)
EnsemblGeneIds (GRCh38): ENSG00000155966
EnsemblGeneIds (GRCh37): ENSG00000155966
OMIM: 300806, Gene2Phenotype
AFF2 is in 3 panels

3 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Intellectual developmental disorder, X-linked 109 (OMIM:3095480, is also associated with deletions of AFF2. Stettner et al. (PMID: 21739600) describe 2 brothers with OMIM:3095480, who have a 121 to 145-kb intragenic deletion within AFF2, while Sahoo et al (PMID: 22065534) report two unrelated males with OMIM:3095480; Patient 1 has a 240 kb intragenic deletion resulting the loss of exons 2-4 of AFF2 and Patient 2 has a 499 kb deletion that removes the exons 1-2.
Created: 25 Jun 2024, 9:51 a.m. | Last Modified: 25 Jun 2024, 9:51 a.m.
Panel Version: 4.5
The association of AFF2 variants with Intellectual developmental disorder, X-linked 109 (OMIM:309548) / FRAXE intellectual disability (MONDO:0010659) has been established, with a Definitive rating in Gen2Phen and in Gene-Disease Validity in ClinGen.
The summary from the ClinGen classification is given below, including the PMID IDs for the relevant literature:

AFF2 variants were first reported in relation to X-linked non-syndromic intellectual disability in 1993 (PMID:8334699). This gene encodes a putative transcriptional activator involved in speckle biogenesis. AFF2, previously referred to as FMR2, is associated with the folate-sensitive fragile X E locus on chromosome X. An expansion of the GCC trinucleotide repeat in this gene leads to Fragile XE syndrome, or FRAXE, a form of X-linked intellectual disability. Individuals with variants in AFF2 commonly present with intellectual disability, seizures, behavioral manifestations, and mild dysmorphic facial features.
AFF2 is highly constrained for LoF variants (gnomAD v2.1.1). The repeat expansion, c.-460_-458GCC(6_25), is reported in at least six probands in three publications (PMIDs: 8334699, 8023854, 21739600) and is included in this curation. One additional missense variant (PMID:21739600) is included in this curation.
This gene-disease relationship is also supported by functional expression experimental evidence, a drosophila rescue, mouse model, protein interaction, biochemical function, and patient cell alteration evidence (PMIDs: 9299237, 11171404, 11923441, 19136466, 23562910).
In summary, there is a definitive gene-disease relationship between AFF2 and X-linked non-syndromic intellectual disability. This classification was originally approved by the Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017. As of June 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added. (Gene Clinical Validity Standard Operating Procedures
(SOP) - SOP9).
Created: 17 Jun 2024, 1:47 p.m. | Last Modified: 17 Jun 2024, 1:47 p.m.
Panel Version: 4.4

Publications

Created: 17 Jun 2024, 1:47 p.m.
Last Modified: 17 Jun 2024, 1:47 p.m.
Panel version: 4.5

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

The DDG2P confidence category for the disease FRAGILE X-E INTELLECTUAL DEVELOPMENTAL DISORDER SYNDROME, OMIM:309548 is definitive. The allelic requirement and mutation consequence are monoallelic_X_hem and absent gene product (PMIDs: 21739600;8334699).
Created: 4 Oct 2023, 5:08 p.m. | Last Modified: 4 Oct 2023, 5:08 p.m.
Panel Version: 3.12

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
FRAGILE X-E INTELLECTUAL DEVELOPMENTAL DISORDER SYNDROME, OMIM:309548

Publications

Created: 4 Oct 2023, 5:08 p.m.
Last Modified: 4 Oct 2023, 5:08 p.m.
Panel version: 3.12

Rebecca Foulger (Genomics England curator)

I don't know

Original DDG2P rating: confirmed.
Created: 19 Nov 2018, 11:29 a.m.
Created: 19 Nov 2018, 11:29 a.m.

Panel version: 0.2

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • DD-Gene2Phenotype
  • Expert Review Green
Phenotypes
  • Intellectual developmental disorder, X-linked 109, OMIM:309548
  • FRAXE intellectual disability, MONDO:0010659
Tags
nucleotide-repeat-expansion
OMIM
300806
Clinvar variants
Variants in AFF2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

25 Jun 2024, Gel status: 3

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: AFF2 were set to 8334699; 8023854; 21739600; 9299237; 11171404; 11923441; 19136466; 2356291

17 Jun 2024, Gel status: 3

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: AFF2 were set to 8334699; 21739600

17 Jun 2024, Gel status: 3

Added Tag

Sarah Leigh (Genomics England Curator)

Tag nucleotide-repeat-expansion tag was added to gene: AFF2.

17 Jun 2024, Gel status: 3

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: AFF2 were changed from FRAGILE X-E MENTAL RETARDATION SYNDROME 309548 to Intellectual developmental disorder, X-linked 109, OMIM:309548; FRAXE intellectual disability, MONDO:0010659

4 Oct 2023, Gel status: 3

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: AFF2 were updated from 21739600; 8334699 to 8334699; 21739600

29 Jan 2019, Gel status: 4

Panel promoted to version 1.0

Rebecca Foulger (Genomics England curator)

Rebecca Foulger: Original DDG2P rating: confirm

19 Nov 2018, Gel status: 4

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Rebecca Foulger (Genomics England curator)

gene: AFF2 was added gene: AFF2 was added to DDG2P. Sources: Expert Review Green,DD-Gene2Phenotype Mode of inheritance for gene: AFF2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: AFF2 were set to 21739600; 8334699 Phenotypes for gene: AFF2 were set to FRAGILE X-E MENTAL RETARDATION SYNDROME 309548