Mendeliome
Gene: WDR11 Green List (high evidence)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.
-----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
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
Gene: wdr11 has been classified as Green List (High Evidence).
Phenotypes for gene: WDR11 were changed from to Intellectual disability; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Publications for gene: WDR11 were set to
Mode of inheritance for gene: WDR11 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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
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 panelapp@genomicsengland.co.uk
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.