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Intellectual disability

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

5 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, 9:50 a.m. | Last Modified: 25 Jun 2024, 9:50 a.m.
Panel Version: 6.38
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, 1:46 p.m. | Last Modified: 17 Jun 2024, 1:46 p.m.
Panel Version: 6.23

Publications

Created: 17 Jun 2024, 1:46 p.m.
Last Modified: 17 Jun 2024, 1:46 p.m.
Panel version: 6.38

Caroline Wright (Sanger)

Green List (high evidence)

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

Phenotypes
FRAGILE X-E MENTAL RETARDATION SYNDROME (FRAXE)

Publications

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_gilissen_2014_known;in_UKGTN_v12 . Main mutation mechanism : Loss of function
Created: 27 Jul 2017, 5 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; find_uk10k; gilissen_2014_known; sfari_20150206; UKGTN_v12; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_green_20160217; neuro_20160418_strict; Loss of function. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 11:55 a.m.

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

Publications

Created: 2 Aug 2017, 1:58 p.m.

Panel version: 1.354

Alice Gardham (Genomics England)

Comment on mode of pathogenicity: Nucleotide repeat expansion in some, deletion in other. Tagged 5.12.16 by Alice Gardham
Created: 5 Dec 2016, 11:54 a.m.
Created: 5 Dec 2016, 11:54 a.m.

Panel version: 1.18

Lu Raymond (university of cambridge )

Green List (high evidence)

Created: 23 Feb 2016, 10:55 a.m.

Panel version: 0.306

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Victorian Clinical Genetics Services
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
  • Emory Genetics Laboratory
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
Complete
Publications
Mode of Pathogenicity
Other - please provide details in the comments
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 25529582; 24896178; 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 21739600; 8334699; 25529582; 24896178

17 Jun 2024, Gel status: 3

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: AFF2 were changed from Intellectual developmental disorder, X-linked 109, OMIM:309548; Fragile XE syndrome (FRAXE) to Intellectual developmental disorder, X-linked 109, OMIM:309548; FRAXE intellectual disability, MONDO:0010659

17 Jun 2024, Gel status: 3

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: AFF2 were set to 21739600; 8334699

17 Jun 2024, Gel status: 3

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: AFF2 were set to

4 Mar 2024, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: AFF2 were changed from Mental retardation, X-linked, FRAXE type, 309548; FRAXE Syndrome; FRAGILE X-E MENTAL RETARDATION SYNDROME (FRAXE) to Intellectual developmental disorder, X-linked 109, OMIM:309548; Fragile XE syndrome (FRAXE)

28 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to AFF2.

12 Mar 2018, Gel status: 3

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

5 Dec 2016, Gel status: 4

Set mode of pathogenicity

Alice Gardham (Genomics England)

Mode of pathogenicity for AFF2 was changed to Other - please provide details in the comments

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 4

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 3

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

AFF2 was added to Intellectual disabilitypanel. Source: Expert Review Green Model of inheritance for gene AFF2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females

24 Jun 2015, Gel status: 3

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene AFF2 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females

24 Jun 2015, Gel status: 3

Added New Source

Ellen McDonagh (Genomics England Curator)

AFF2 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,UKGTN,Radboud University Medical Center, Nijmegen

24 Jun 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene AFF2 was changed to X-LINKED: hemizygous mutation in males, may be caused by monoallelic mutations in females

24 Jun 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

AFF2 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,UKGTN,Radboud University Medical Center, Nijmegen

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

AFF2 was added to Intellectual disabilitypanel. Sources: Emory Genetics Laboratory,UKGTN,Radboud University Medical Center, Nijmegen