Intellectual disability
Gene: WDR11

WDR11 (WD repeat domain 11)
EnsemblGeneIds (GRCh38): ENSG00000120008
EnsemblGeneIds (GRCh37): ENSG00000120008
OMIM: 606417, Gene2Phenotype
WDR11 is in 7 panels

6 reviews

Ivone Leong (Genomics England Curator)

Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in Gene2Phenotype (probable) but not in OMIM. There is enough evidence to support a gene-disease association; however, the severity of ID in the patients described in PMID:34413497 does not fit the criteria for this panel (panel is for moderate to severe ID, patients have mild ID). Therefore, this gene has been given an Amber rating.

The OFC of patients in PMID: 34413497 ranged from -3.09 SD to -4.93 SD)
Created: 11 Oct 2021, 1:18 p.m. | Last Modified: 11 Oct 2021, 1:18 p.m.

Panel Version: 3.1348

Comment on phenotypes: Previously associated with Kallmann syndrome.
Created: 11 Oct 2021, 1:14 p.m. | Last Modified: 11 Oct 2021, 1:14 p.m.

Panel Version: 3.1347

Comment on mode of inheritance: Changed MOI from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BIALLELIC, autosomal or pseudoautosomal" as biallelic variants in this gene is associated with ID.
Created: 11 Oct 2021, 1:12 p.m. | Last Modified: 11 Oct 2021, 1:12 p.m.

Panel Version: 3.1345

Created: 11 Oct 2021, 1:12 p.m.
Last Modified: 11 Oct 2021, 1:12 p.m.
Panel version: 3.1345

Konstantinos Varvagiannis (Other)

I don't know

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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The authors discuss briefly on the previously proposed role for WDR11 in endosome to trans Golgi network vesicular trafficking which might also be supported by their colocalization experiments in patient fibroblasts.
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Consider inclusion in the ID panel with amber/green rating.
Created: 22 Aug 2021, 4:40 p.m. | Last Modified: 22 Aug 2021, 4:40 p.m.

Panel Version: 3.1238

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability; Microcephaly; Short stature

Publications

34413497

Created: 22 Aug 2021, 4:40 p.m.
Last Modified: 22 Aug 2021, 4:40 p.m.
Panel version: 3.1238

Caroline Wright (Sanger)

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
KALLMANN SYNDROME

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Rebecca Foulger (Genomics England curator)

Red List (low evidence)

Confirmed DD-G2P gene for 'Kallmann syndrome' (Orphanet:478) which is hypogonadotropic hypogonadism (MIM:614858) accompanied by anosmia, and is characterised by delayed or absent puberty. Although catergorised as a 'known ID gene' in PMID:24896178 (Gilissen et al., 2014), WDR11 variants are not recorded in De Ligt et al., 2012 (PMID:23033978) on which part of the Gilissen list is based, and no further literature evidence for involvement of WDR11 in ID.
Created: 31 Oct 2017, 9:24 a.m.

Publications

26350204

Created: 31 Oct 2017, 9:24 a.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.4

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_gilissen_2014_known . Main mutation mechanism : All missense/in frame
Created: 27 Jul 2017, 8:54 p.m.

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

Publications

Mode of pathogenicity
Other

Created: 2 Aug 2017, 11:25 p.m.

Panel version: 1.354

Lu Raymond (university of cambridge )

I don't know

Created: 23 Feb 2016, 10:15 a.m.

Panel version: 0.306

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber

Phenotypes

Intellectual disability, MONDO:0001071
Microcephaly, MONDO:0001149
Short stature,HP:0004322

Tags

watchlist

OMIM

606417

Clinvar variants

Variants in WDR11

Penetrance

Complete

Publications

Panels with this gene