Intellectual disability - microarray and sequencing
Gene: ZMYM2
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
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
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
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
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: LiteratureCreated: 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
Tag Q3_22_rating was removed from gene: ZMYM2. Tag Q3_22_NHS_review was removed from gene: ZMYM2.
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)
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
Tag Q3_22_rating tag was added to gene: ZMYM2. Tag Q3_22_NHS_review tag was added to gene: ZMYM2.
Gene: zmym2 has been classified as Amber List (Moderate Evidence).
Gene: zmym2 has been classified as Amber List (Moderate Evidence).
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