Intellectual disability - microarray and sequencing
Gene: ZMIZ1 Green List (high evidence)Comment on list classification: Gene ZMIZ1 identified by expert review by Konstantinos Varvagiannis on Carapito et al. (PMID: 30639322) who reported on 19 individuals, 16 unrelated, with variants affecting ZMIZ1. Apart from one family (3 individuals) for whom parental samples were unavailable, all variants were shown to be de novo.
The phenotype is broad and there are few consistent features throughout the subjects, however all individuals are reported to have ID, varying in severity.
ZMIZ1 is probable in Gene2Phenotype although a list of phenotypes have not been assigned to the G2P entry and currently not associated with any phenotypes in OMIM.
As sufficient number of subjects and ID is consistent throughout there is sufficient evidence to class ZMIZ1 as Green.Created: 23 May 2019, 3 p.m. | Last Modified: 17 Jul 2019, 12:42 p.m.
Panel Version: 0.200
Green List (high evidence)
Carapito et al. (doi.org/10.1016/j.ajhg.2018.12.007 - PMID to add) report on 19 individuals with variants affecting ZMIZ1 (alternative symbols RAI17/KIAA1224/ZIMP10).
Features included DD/ID (19/19), feeding difficulties, growth failure, microcephaly and variable congenital malformations. Seizures were noted in 3 unrelated individuals (with different variants).
Variants included 6 missense SNVs, 5 frameshift variants, 1 splice site variant, 1 synonymous variant with probable impact on splicing (not studied) and 2 translocations.
In all individuals for whom parental studies were possible (n=16), the variants had occurred as de novo events while for 3 sibs harboring a frameshift variant parental samples were unavailable. These subjects however harbored the same variant as a DDD study participant included in the current report.
One translocation disrupted only ZMIZ1 while a second [t(X;10)] did not disrupt the coding sequence of any gene but only a distal enhancer 276 kb upstream of ZMIZ1. A previous study had found recurrent SNVs of the same region in ASD subjects and suggested possible interaction with the ZMIZ1 promoter (Liu et al. - PMID: 29754769).
The deleterious effect of both translocations was confirmed by quantitative RT-PCR. For 4 missense SNVs as well as a splice variant mRNA levels were similar to controls. The splice site (-2) variant was shown to produce 2 new splicing isoforms from utilization of alternative splice site acceptors.
ZMIZ1 belongs to the PIAS-like family of transcriptional coregulators.
Five missense variants were located in an alanine rich domain (aa 280-305). Seven other variants were predicted to shorten or remove the C-terminal transactivation domain.
This gene enhances - among others - the transcriptional activity of androgen receptor (AR). In vitro studies using HEK293T cell lines supported impaired coactivation of the AR for 3 variants studied. In utero electroporation of pathogenic variants in mouse embryos (E14.5) led to impaired neuronal positioning of the electroporated neurons and disruption of the morphology/polarization.
As the authors note previous studies have shown expression of Zimp10 in the developing mouse brain, craniofacial tissue as well as the interdigital region of limbs (PMIDs cited : 18053775 and 17967885) in line with ID, facial phenotype and syndactyly observed in some patients.
Finally the authors cite a previous report on an individual with ID due to a translocation [t(10;19)] disrupting both ZMIZ1 and PRR12 (Córdova-Fletes al. - PMID: 26163108). Although disruption of ZMIZ1 is discussed as a cause, PRR12 has recently been proposed as (also) an ID gene (Leduc et al. - PMID: 29556724). [For details see PRR12 in the current panel].
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One of the variants found in 2 unrelated individuals in the aforementioned study [NM_020338.3:c.899C>T or p.(T300M)] has been reported in a further individual investigated for ID in the context of a bigger cohort (Lelieveld et al. - PMID: 27479843).
[ Details in the denovo-db : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZMIZ1 ]
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ZMIZ1 is not associated with any phenotype in OMIM, nor in G2P.
This gene has been included in gene panels for intellectual disability offered by some diagnostic laboratories.
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As a result, ZMIZ1 can be considered for inclusion in the ID panel as green.
Sources: LiteratureCreated: 12 Jan 2019, 2:50 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Global developmental delay; Intellectual disability; Feeding difficulties; Growth abnormality; Microcephaly; Abnormality of the skeletal system; Abnormality of the urinary system; Abnormality of the cardiovascular system; Abnormality of head or neck
Publications
Variants in this GENE are reported as part of current diagnostic practice
Source Expert Review Green was added to ZMIZ1. Source Expert Review was added to ZMIZ1. Added phenotypes Global developmental delay, Intellectual disability, Feeding difficulties, Growth abnormality, Microcephaly, Abnormality of the skeletal system, Abnormality of the urinary system, Abnormality of the cardiovascular system, Abnormality of head or neck for gene: ZMIZ1 Publications for gene ZMIZ1 were changed from 29754769; 18053775; 17967885; 26163108; 27479843 to 29754769; 18053775; 17967885; 30639322; 26163108; 27479843 Rating Changed from No List (delete) to Green List (high evidence)
gene: ZMIZ1 was added gene: ZMIZ1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ZMIZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZMIZ1 were set to 29754769; 18053775; 17967885; 26163108; 27479843 Phenotypes for gene: ZMIZ1 were set to Global developmental delay; Intellectual disability; Feeding difficulties; Growth abnormality; Microcephaly; Abnormality of the skeletal system; Abnormality of the urinary system; Abnormality of the cardiovascular system; Abnormality of head or neck Penetrance for gene: ZMIZ1 were set to unknown Review for gene: ZMIZ1 was set to GREEN gene: ZMIZ1 was marked as current diagnostic
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 [email protected]
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.