Genes in panel

STRs in panel

Prev Next

Regions in panel

Prev Next

Intellectual disability
Gene: AFF3

AFF3 (AF4/FMR2 family member 3)
EnsemblGeneIds (GRCh38): ENSG00000144218
EnsemblGeneIds (GRCh37): ENSG00000144218
OMIM: 601464, Gene2Phenotype
AFF3 is in 5 panels

4 reviews

Arina Puzriakova (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, imprinted status unknown' following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.

Panel Version: 4.53

Removed watchlist tag as the Voisin et al. 2021 paper has now been published (PMID: 33961779) and this gene should be promoted to Green at the next GMS review.
Created: 11 Apr 2022, 2:18 p.m. | Last Modified: 11 Apr 2022, 2:18 p.m.

Panel Version: 3.1546

Created: 11 Apr 2022, 2:18 p.m.
Last Modified: 11 Apr 2022, 2:18 p.m.
Panel version: 4.53

Sarah Leigh (Genomics England Curator)

I don't know

Not associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Skeletal dysplasia with severe neurological disease. At least 2 variants have been reported in peer reviewed literature, further four variants have been reported in a preprint (July 2019). This preprint has not been published in a peer reviewed (as of 06/08/2020). There are convincing aminal models. If the preprint is peer reviewed and the evidence is relevant, then this gene could be rated green at the next major review (as of 12/11/2020).
Created: 6 Aug 2020, 3:21 p.m. | Last Modified: 12 Nov 2020, 2:23 p.m.

Panel Version: 3.520

Created: 6 Aug 2020, 3:21 p.m.
Last Modified: 12 Nov 2020, 2:23 p.m.
Panel version: 3.237

Rebecca Foulger (Genomics England curator)

As noted by Konstantinos Varvagiannis, Voisin et al., 2019 (not yet in PubMed) describe de novo missense variants in the degron of AFF3 (a region required for its degradation) in 10 unrelated individuals with symptoms including ID. 4 different missense variants were identified (p.A258S, p.A258T, p.A258V and p.V260G). Although there are sufficient cases with a relevant phenotype (plus the individual reported in PMID:18616733), I have rated as Amber pending publication of the Voisin 2019 article: as OMIM note in their correspondance on AFF3, information changes from the initial bioRxiv upload to peer-reviewed publication. Therefore updated rating of AFF3 from Red to Amber, added 'watchlist' tag and 'missense' tag, and will re-curate when the paper is published.
Created: 15 Aug 2019, 12:31 p.m. | Last Modified: 15 Aug 2019, 12:41 p.m.

Panel Version: 2.1004

Created: 15 Aug 2019, 12:31 p.m.
Last Modified: 15 Aug 2019, 12:41 p.m.
Panel version: 2.1000

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb deletion affecting only AFF3 (LAF4) and removing also this sequence.

The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy].

9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13.

AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development.

Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot.

Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study].

Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects.

Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant.

Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3.
----
Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)].
----
In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM.
Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel).
----
As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).

[Review modified to add additional reference/case report]
Created: 7 Aug 2019, 5:30 p.m. | Last Modified: 10 Dec 2019, 12:40 p.m.

Panel Version: 2.1143

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Intellectual disability; Seizures; Abnormality of skeletal morphology; Abnormality of the urinary system; Hypertrichosis; Abnormality of the respiratory system

Publications

https://doi.org/10.1101/693937
18616733

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

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

Created: 7 Aug 2019, 5:30 p.m.
Last Modified: 10 Dec 2019, 12:40 p.m.
Panel version: 2.996

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Green
NHS GMS
Victorian Clinical Genetics Services

Phenotypes

KINSSHIP syndrome, OMIM:619297

Tags

missense

OMIM

601464

Clinvar variants

Variants in AFF3

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

History Filter Activity

31 Jan 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review was removed from gene: AFF3.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to AFF3. Source Expert Review Green was added to AFF3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

11 Apr 2022, Gel status: 2

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist was removed from gene: AFF3.

11 Apr 2022, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733; 21677750; 25660031; 31388108

11 Apr 2022, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: AFF3 were changed from Intellectual disability; Seizures to KINSSHIP syndrome, OMIM:619297

12 Nov 2020, Gel status: 2

Added Tag

Sarah Leigh (Genomics England Curator)

Tag for-review tag was added to gene: AFF3.

6 Aug 2020, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733

15 Aug 2019, Gel status: 2