Intellectual disabilityGene: WDR37
Added missense tag: only missense variants reported so far (PMID:31327510 and PMID:31327508).
Created: 15 Aug 2019, 12:17 p.m. | Last Modified: 15 Aug 2019, 12:17 p.m.
Panel Version: 2.1000
WDR37 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Although WDR37 is not yet associated with a disorder in OMIM or Gene2Phenotype, there are sufficient unrelated cases in two recent papers (PMID:31327510 and PMID:31327508) with a severe ID/DD phenotype for inclusion on the panel. Plus it was agreed at the Webex call on Thurs 8th August with members of the GMS Neurology Specialist Test Group that WDR37 should be rated Green on the epilepsy panel (402). Therefore updated rating from Grey to Green.
Created: 15 Aug 2019, 12:05 p.m. | Last Modified: 15 Aug 2019, 12:05 p.m.
Panel Version: 2.999
PMID:31327508: Kanca et al., 2019 report 5 individuals with missense de novo WDR37 variants. Developmental delay and ID was recorded in 4 of the probands (and was severe in several cases). Proband 5 was too young for DD/ID evaluation.
Although not explicitly stated, the probands appear to be unrelated.
Created: 15 Aug 2019, 11:59 a.m. | Last Modified: 15 Aug 2019, 11:59 a.m.
Panel Version: 2.999
Two concurrent publications by Reis et al. and Kanca et al. (2019 - PMIDs: 31327510, 31327508) report on the phenotype of individuals with de novo WDR37 mutations.
The study by Reis et al. provides clinical details on 4 affected individuals, while 5 further are described by Kanca et al.
4 different de novo variants were reported in these individuals who appear to be unrelated in (and between) the 2 studies [NM_014023.3]:
- c.356C>T (p.Ser119Phe) [Reis indiv. 1 - 3y, Kanca proband 3 - 5m2w]
- c.389C>T (p.Thr130Ile) [Reis indiv. 2 - 22m , Kanca proband 5 - 6w]
- c.374C>T (p.Thr125Ile) [Reis indiv. 3 - 8y , Kanca proband 1 - 7y]
- c.386C>G (p.Ser129Cys) [Reis indiv. 4 - unkn age, Kanca probands 2 and 4, 6.5y and 19y]
Common features included DD/ID (severity relevant for the current panel), seizures (9/9), ocular anomalies (corneal opacity/Peters anomaly, coloboma, microphthalmia etc.) and variable brain, hearing, cardiovascular, skeletal and genitourinary anomalies. Some facial and/or other dysmorphic features (incl. excess nuchal skin / webbed neck) were also frequent among affected individuals. Feeding difficulties and growth deficiency were also among the features observed.
The function of WDR37 is not known. Variants demonstrated comparable protein levels and cellular localization compared to wt.
Reis et al. provide evidence using CRISPR-Cas9 mediated genome editing in zebrafish, to introduce the Ser129Cys variant observed in affected individuals as well as novel missense and frameshift variants. Poor growth (similar to the human phenotype) and larval lethality were noted for missense variants. Head size was proportionately small. Ocular (coloboma/corneal) or craniofacial anomalies were not observed. Zebrafish heterozygous for LoF variants survived to adulthood.
Based on these a dominant-negative mechanism was postulated for missense alleles.
RNA-seq analysis in zebrafish showed upregulation of cholesterol biosynthesis pathways (among the most dysregulated ones).
Previous data in mice, suggest a broad expression pattern for Wdr37 with enrichment in ocular and brain tissues, significant associations in homozygous mutant mice for decreased body weight, grip strength, skeletal anomalies and possible increase (p =< 0.05) in ocular (lens/corneal) and other anomalies [BioGPS and International Mouse Phenotyping Consortium cited].
CG12333 loss (the Drosophila WDR37 ortholog) causes increased bang sensitivity in flies (analogous to the human epilepsy phenotype), defects in copulation and grip strength, phenotypes that were rescued by human reference but not variant cDNAs.
As discussed by Kanca et al. based on data from Drosophila and mice, limited phenotypic similarity of CNVs spanning WDR37 and adjacent genes with the reported individuals and the presence of LoF variants in control populations haploinsufficiency appears unlikely. Gain-of-function is also unlikely, as expression of human variants in flies did not exacerbate the observed phenotypes. A dominant-negative effect is again proposed.
WDR37 is not associated with any phenotype in OMIM/G2P.
As a result WDR37 can be considered for inclusion in the ID and epilepsy panels with green (relevant phenotype, sufficient cases, animal models) or amber rating.
Created: 7 Aug 2019, 5:06 p.m. | Last Modified: 7 Aug 2019, 5:06 p.m.
Panel Version: 2.996
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Gene: wdr37 has been classified as Green List (High Evidence).
Mode of pathogenicity for gene: WDR37 was changed from None to Other
Tag missense tag was added to gene: WDR37.
gene: WDR37 was added gene: WDR37 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WDR37 were set to 31327510; 31327508 Phenotypes for gene: WDR37 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system Penetrance for gene: WDR37 were set to unknown Review for gene: WDR37 was set to GREEN