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Intellectual disability

Gene: WDFY3

Amber List (moderate evidence)

WDFY3 (WD repeat and FYVE domain containing 3)
EnsemblGeneIds (GRCh38): ENSG00000163625
EnsemblGeneIds (GRCh37): ENSG00000163625
OMIM: 617485, Gene2Phenotype
WDFY3 is in 4 panels

5 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: There is a sufficient number of cases with moderate ID to meet the threshold for inclusion on a diagnostic ID panel. Furthermore, ID is currently the most applicable clinical indication for detecting these cases using PanelApp panels.

Therefore, recommending a rating upgrade from Amber to Green at the next major review.
Created: 21 Sep 2020, 11 a.m. | Last Modified: 21 Sep 2020, 11 a.m.
Panel Version: 3.320

Ivone Leong (Genomics England Curator)

Comment on list classification: Gene promoted from Red to Amber based on evidence provided by expert reviewer. All affected individuals have mild-moderate ID, therefore the gene has been rated Amber.
Created: 26 Nov 2019, 4:08 p.m. | Last Modified: 26 Nov 2019, 4:08 p.m.
Panel Version: 2.1122

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Heterozygous pathogenic WDFY3 (alternative symbol: ALFY) variants have been reported in several individuals with abnormal head circumference and mild-moderate ID, although the latter was not a feature in all :

[1] PMID: 27008544 (Kadir et al. 2016) - A large 3-generation pedigree with several individuals with microcephaly and mild-moderate ID.
[2] PMID: 31327001 (De Luc et al. 2019) - 13 individuals (11/13 with dn variants) with mild to moderate ID (in 8/10 assessed, 2/10 had normal functioning, 3 were not assessed).

Several de novo variants have been previously identified in ASD cohorts (summarized in ref2 - fig1) while ASD was also among the features in more detailed clinical reports (eg. in 7/12 subjects in ref2).

Variants occurred mostly as de novo events. In cases of inherited variants segregation with the disorder (abnormal OFC and ID) was compatible (refs1,2 - a LOD score of 3.44 calculated in ref1) although in one case parental status was not assessed (ref2).

A different effect of missense variants in the PH-domain and truncating variants or missense in the BEACH domain has been suggested to reflect micro-/macro-cephaly phenotypes although the number of variants is small (only 2 variants in the PH-domain in individuals with microcephaly - one had a 2nd/concurrent diagnosis not explaining this feature, macrocephaly in individuals with truncating / missense in the BEACH domain).

WDFY3 appears to be intolerant to both missense/LoF variants (Z-score of 5.82 and pLI of 1 in gnomAD).

Prenatal expression in human brain has been shown (ref2).

Animal models (drosophila and mouse) support a role in proper embryonic brain development and size probably due to dysregulation of Wnt signalling (heterozygous models studied in ref1, ref2, a knock-out mouse model was previously reported in PMID: 25198012). Further, heterozygous mice displayed impaired motor coordination and associative learning deficits (ref2) and bchs-deficient flies show defects in habituation (PMID: 28191889 cited - bchs is the Drosophila WDFY3 ortholog).

In OMIM the WDFY3-related phenotype is ?Microcephaly 18, primary, autosomal dominant (MIM 617520) [only ref1 was considered].

WDFY3 is included in the DD panel of G2P, associated with 'Primary Microcephaly or macrocephaly with developmental delay'.

The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).

Overall, WDFY3 could be considered for upgrade to green (ID is a feature in >3 individuals/families/variants, expression pattern, animal models, etc.) or amber (ID in most but not all subjects, mild-moderate in all cases).
Created: 11 Nov 2019, 5:26 p.m. | Last Modified: 11 Nov 2019, 5:26 p.m.
Panel Version: 2.1098

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

Phenotypes
?Microcephaly 18, primary, autosomal dominant - MIM 617520

Publications

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

Louise Daugherty (Genomics England Curator)

Comment on phenotypes: added OMIM MIMid
Created: 16 Jul 2018, 1:24 p.m.
Comment on list classification: New gene added by external expert review, but notes there is not enough evidence to promote this gene from Red rating. Kadir et al. (2016, PMID:27008544) describes a large kindred presented with autosomal dominant isolated primary microcephaly with mild to moderate intellectual disability and identified a heterozygous c.7909C-T transition in WDFY3.
Created: 16 Jul 2018, 1:23 p.m.

Zornitza Stark (Australian Genomics)

Green List (high evidence)

>10 individuals with heterozygous variants in this gene and mild/moderate intellectual disability now described in the literature. Some evidence for opposing effects on brain size depending on variant location.
Created: 2 Mar 2020, 7:56 a.m. | Last Modified: 2 Mar 2020, 7:56 a.m.
Panel Version: 3.3
One affected individual reported, with functional evidence. Consider inclusion as Red.
Created: 22 Jun 2018, 3:08 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Microcephaly 18, primary, autosomal dominant

Publications

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Microcephaly 18, primary, autosomal dominant, 617520
Tags
for-review
OMIM
617485
Clinvar variants
Variants in WDFY3
Penetrance
None
Publications
Panels with this gene

History Filter Activity

21 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: wdfy3 has been classified as Amber List (Moderate Evidence).

21 Sep 2020, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: WDFY3.

26 Nov 2019, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: wdfy3 has been classified as Amber List (Moderate Evidence).

26 Nov 2019, Gel status: 1

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: WDFY3 were set to 27008544

29 Sep 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to WDFY3.

16 Jul 2018, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: WDFY3 were set to Microcephaly 18, primary, autosomal dominant, 617520

16 Jul 2018, Gel status: 1

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: wdfy3 has been classified as Red List (Low Evidence).

22 Jun 2018, Gel status: 0

Added New Source

Zornitza Stark (Australian Genomics)

WDFY3 was added to Intellectual disability panel. Sources: Literature

22 Jun 2018, Gel status: 0

Created

Zornitza Stark (Australian Genomics)

WDFY3 was created by Zornitza Stark