Intellectual disability
Gene: WDFY3 Green List (high evidence)The 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
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
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.
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
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
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.