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Mendeliome

Gene: WDR11

Green List (high evidence)

WDR11 (WD repeat domain 11)
EnsemblGeneIds (GRCh38): ENSG00000120008
EnsemblGeneIds (GRCh37): ENSG00000120008
OMIM: 606417, Gene2Phenotype
WDR11 is in 8 panels

1 review

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

Haag et al (2021 - PMID: 34413497) report on 6 individuals from 3 unrelated families, harboring biallelic LoF WDR11 variants.

Common features included microcephaly (6/6 - range: -2.43 SD to -4.93SD) and intellectual disability (6/6, in 5 cases mild, in 1 severe) with some individuals presenting also with mild short stature.

Homozygosity or compound heterozygosity for LoF variants in affected individuals was identified following exome sequencing (fam1: NM_018117.12:c.1255C>T/p.Q419* hmz, fam2:c.3033_3036del/D1011Efs*21 in trans with c.1439del/p.N480Tfs*32, fam3:c.2931+1G>A hmz).

Segregation studies supported carrier state of parents and unaffected sibs (or homozygosity for wt allele in the latter).

Variable previous investigations incl. standard karyotype and CMA were normal in several subjects (notably index cases from each family).
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As the authors comment WDR11 encodes for the WD repeat domain 11 protein and has broad expression in the developing mouse CNS. Mutations in other genes encoding for WD repeat proteins have been associated with neurological, endocrine or other disorders incl. ciliopathies.

Heterozygous missense WDR11 variants are associated with hypogonadotropic hypogonadism (HH) 14 with or without anosmia (MIM #614858). [Gene2Phenotype : monoallelic, all missense/in-frame].

The authors performed extensive hormonal studies and argue that the phenotype associated with biallelic variants differs significantly from the dominantly inherited variants (HH) suggesting that biallelic variants result in a clinically distinct entity. In addition, carrier parents of the individuals reported by Haag et al had no obvious signs of congenital HH. However, there was no endocrinological examination performed.
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Variant effect:
Immunofluorescence studies demonstrated strong juxtanuclear WDR11 staining in control fibroblasts , but only cell-ubiquitous background labeling in patient fibroblasts (for Q419*). There was also evidence for colocalization of wt WDR11 to the trans-Golgi network (TGN) with loss of this pattern in patient fibroblasts (Q419*).

Western blot in whole cell lysates of cultured patient fibroblasts (same variant) proved loss of WDR11 irrespectively of the antibody used (against N- or C-terminal epitopes of WDR11). There was no indication of a truncated protein.
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Animal models:
The authors discuss previous evidence from mice/zebrafish models suggesting abnormal Hedgehog signaling in the primary cilium and impaired ciliogenesis due to loss of WDR11.

Wdr11-null mice display features of holoprosencephaly incl. microcephaly, hypotelorism, micro/anophthalmia, abnormal pituitary gland, growth retardation, heart defects, hypoplasia of reproductive organs and infertility. There was evidence of reduced length of the ciliary axoneme and reduced frequency of ciliated cells.

Knockdown of wdr11 in zebrafish led to microcephaly, aberrant head cartilage formation, microphthalmia, curved body axis, motility defects.

Overall the authors consider that the phenotype of microcephaly, variable growth delay and/or some visual/skeletal anomalies are recapitulated to some degree in animal models, although a more severe phenotype is observed in mice.

In the cohort presented by Haag et al there was no evidence of congenital heart defects, brain malformations, abnormal sexual hormone profiles or pituitary (MRI) abnormalities based on the investigations performed.
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Created: 23 Aug 2021, 2:13 a.m. | Last Modified: 23 Aug 2021, 2:13 a.m.
Panel Version: 0.8914

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • Intellectual developmental disorder, autosomal recessive 78, MIM# 620237
  • Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
OMIM
606417
Clinvar variants
Variants in WDR11
Penetrance
None
Publications
Panels with this gene

History Filter Activity

9 Feb 2023, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: WDR11 were changed from Intellectual disability; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858 to Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858

23 Aug 2021, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: wdr11 has been classified as Green List (High Evidence).

23 Aug 2021, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: WDR11 were changed from to Intellectual disability; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858

23 Aug 2021, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: WDR11 were set to

23 Aug 2021, Gel status: 3

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: WDR11 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

17 Nov 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: WDR11 was added gene: WDR11 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: WDR11 was set to Unknown