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Intellectual disability - microarray and sequencing

Gene: WDR11

Amber List (moderate evidence)

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

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

Caroline Wright (Sanger)

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
KALLMANN SYNDROME

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

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

Lu Raymond (university of cambridge )

I don't know

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

History Filter Activity

11 Oct 2021, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: wdr11 has been classified as Amber List (Moderate Evidence).

11 Oct 2021, Gel status: 1

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: WDR11 were changed from KALLMANN SYNDROME to Intellectual disability, MONDO:0001071; Microcephaly, MONDO:0001149; Short stature,HP:0004322

11 Oct 2021, Gel status: 1

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: WDR11 were set to 26350204

11 Oct 2021, Gel status: 1

Set mode of inheritance

Ivone Leong (Genomics England Curator)

Mode of inheritance for gene: WDR11 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal

11 Oct 2021, Gel status: 1

Added Tag

Ivone Leong (Genomics England Curator)

Tag watchlist tag was added to gene: WDR11.

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

29 Nov 2017, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene WDR11 was set to ['26350204']

8 Feb 2016, Gel status: 1

Gene classified by Genomics England curator

Richard Scott (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

8 Feb 2016, Gel status: 1

Gene classified by Genomics England curator

Richard Scott (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

WDR11 was added to Intellectual disabilitypanel. Sources: Expert Review Amber

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

WDR11 was created by ellenmcdonagh