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Intellectual disability

Gene: ZMYM2

Green List (high evidence)
ZMYM2 (zinc finger MYM-type containing 2)
EnsemblGeneIds (GRCh38): ENSG00000121741
EnsemblGeneIds (GRCh37): ENSG00000121741
OMIM: 602221, Gene2Phenotype
ZMYM2 is in 5 panels

5 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for ZMYM2-related developmental disorder (monoallelic). At least 3 variants have been reported in cases with mild to unclassified intellectual disability in PMID: 32891193. The review from Tracy Lester (Genetics laboratory, Oxford UK) mentions several additional de novo variants reported by Decipher associated with intellectual / developmental disability.
Created: 14 Jun 2022, 10:46 a.m. | Last Modified: 14 Jun 2022, 10:46 a.m.
Panel Version: 3.1600
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 14 Jun 2022, 10:34 a.m. | Last Modified: 14 Jun 2022, 10:34 a.m.
Panel Version: 3.1600
Created: 14 Jun 2022, 10:34 a.m.
Last Modified: 14 Jun 2022, 10:34 a.m.
Panel version: 3.1600

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

At least 3 cases have been reported with de novo variants in this gene in cases that have intellectual disability/developmental delay as a clinical feature in addition to other syndromic features. There are also several de novo cases in Decipher with ID/DD that support this being a causative gene. for ID that should now be promoted to green for the ID panel.
Created: 7 Jun 2022, 1:59 p.m. | Last Modified: 7 Jun 2022, 1:59 p.m.
Panel Version: 3.1593

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; developmental delay, delayed speech and language, learning disability

Publications

Created: 7 Jun 2022, 1:59 p.m.
Last Modified: 7 Jun 2022, 1:59 p.m.
Panel version: 3.1593

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is probably associated with a phenotype on Gene2Phenotype. This gene has been given an Amber rating based on the expert review and the evidence provided. As ID is not an identifying part of the phenotype and not all affected individuals had ID, this gene has been given an Amber rating.
Created: 12 Nov 2020, 2:22 p.m. | Last Modified: 12 Nov 2020, 2:22 p.m.
Panel Version: 3.520
Created: 12 Nov 2020, 2:22 p.m.
Last Modified: 12 Nov 2020, 2:22 p.m.
Panel version: 3.520

Konstantinos Varvagiannis (Other)

I don't know

Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. DD and ID were reported in some of the families described to date as summarized below. You might consider inclusion with green/amber rating in the ID panel and green in the panel for CAKUT.

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Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. [Article not reviewed in detail].

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Created: 19 Sep 2020, 1:07 a.m.

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

Phenotypes
Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly

Publications

Created: 19 Sep 2020, 1:07 a.m.

Panel version: 3.315

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • NHS GMS
Phenotypes
  • Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, OMIM:619522
OMIM
602221
Clinvar variants
Variants in ZMYM2
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

31 Jan 2023, Gel status: 3

Removed Tag, Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_rating was removed from gene: ZMYM2. Tag Q3_22_NHS_review was removed from gene: ZMYM2.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to ZMYM2. Source Expert Review Green was added to ZMYM2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

14 Jun 2022, Gel status: 2

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: ZMYM2 were changed from Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, OMIM:619522

14 Jun 2022, Gel status: 2

Added Tag, Added Tag

Sarah Leigh (Genomics England Curator)

Tag Q3_22_rating tag was added to gene: ZMYM2. Tag Q3_22_NHS_review tag was added to gene: ZMYM2.

14 Jun 2022, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: zmym2 has been classified as Amber List (Moderate Evidence).

12 Nov 2020, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: zmym2 has been classified as Amber List (Moderate Evidence).

19 Sep 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: ZMYM2 was added gene: ZMYM2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZMYM2 were set to 32891193 Phenotypes for gene: ZMYM2 were set to Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly Penetrance for gene: ZMYM2 were set to unknown Review for gene: ZMYM2 was set to AMBER