Early onset or syndromic epilepsy

Gene: ZMIZ1

I don't know

Kept rating as Amber based on Amber post-Webex review from Helen Lord.

Created: 9 Sep 2019, 10:49 a.m. | Last Modified: 9 Sep 2019, 10:49 a.m.

Panel Version: 1.321

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

I don't know

Not linked to a disease on OMIM. HGMD Pro - asoc with a neurodevelopmental disorder. Carapito et al, 2019 (306393220) - 19 subjects with ID and dev delay. Seizures reported in 3/17 (patient 4, 8 and 17) - of these 14 unrelated subects carried de novo het SNVs or single base ins/dels, 3 siblings harboured a het single base insertion and 2 subjects had a balanced translocation disrupting ZMIZ1. Cordova-Fletes et al, 2015 (26163108) - Girl with ID and neuropsychiatric alterations and seizures since forst week of age (diminished with treatment) with a balanced translocation affecting the ZMIZ1 gene.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

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

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. ZMIZ1 is currently not associated with a disorder in OMIM, it is probable in Gene2Phenotype for Syndromic Neurodevelopmental Disorder although a list of phenotypes have not been assigned to the G2P entry and is based on this paper. Only 3 individuals have seizures and this is not a predominate phenotype within the identified subjects. Therefore ZMIZ1 is classified as Amber until more evidence becomes available.

Created: 25 Jun 2019, 2:46 p.m. | Last Modified: 15 Jul 2019, 9:37 a.m.

Panel Version: 0.72

I don't know

Gene added in the ID panel. Seizures were noted in 3 unrelated individuals (with different variants) of the 19 reported to date. If the proportion of individuals with this feature is sufficient then this gene can be considered for inclusion in this panel.

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From the ID panel:

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: Literature

Created: 12 Jan 2019, 2:58 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; Seizures

Publications

• 29754769
• 18053775
• 17967885
• 26163108
• 27479843