Intellectual disability - microarray and sequencing
Gene: WDFY3The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
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
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
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
Comment on phenotypes: added OMIM MIMidCreated: 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.
>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
Tag for-review was removed from gene: WDFY3.
Source Expert Review Green was added to WDFY3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: wdfy3 has been classified as Amber List (Moderate Evidence).
Tag for-review tag was added to gene: WDFY3.
Gene: wdfy3 has been classified as Amber List (Moderate Evidence).
Publications for gene: WDFY3 were set to 27008544
Source Victorian Clinical Genetics Services was added to WDFY3.
Phenotypes for gene: WDFY3 were set to Microcephaly 18, primary, autosomal dominant, 617520
Gene: wdfy3 has been classified as Red List (Low Evidence).
WDFY3 was added to Intellectual disability panel. Sources: Literature
WDFY3 was created by Zornitza Stark