Intellectual disabilityGene: ZNF462
Comment on list classification: Expert review by Konstantinos Varvagiannis on ZNF462.
Weiss et al. (PMID: 28513610) reports on 8 individuals (from 6 unrelated families) with heterozygous pathogenic variants affecting ZNF462. 4 individuals from 4 families have ID/DD, although one patient had mild ID.
Cosemans et al. (PMID: 29427787) report on an individual with mild ID and ASD, the individual had a de novo (complex) translocation disrupting ZNF462 and KLF12.
A further case of ZNF462 disruption caused by a translocation was published in the literature (Talisetti et al. PMID: 14564155 / Ramocki et al. PMID: 12825074, same individual). Profound ID was among the features of this individual, although the translocation disrupted a further ID gene (ASXL2). There are also further variants reported in the literature, ClinVar and Dechiper.
ZNF462 is probable in the DD panel of G2P, associated with Craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay.
Although ID was not a consistent feature throughout all the individuals reported to have a mutation in ZNF462, there are sufficient number of variants and individuals identified to classify ZNF462 as Green.
Created: 23 May 2019, 2:11 p.m. | Last Modified: 8 Jul 2019, 1:46 p.m.
Panel Version: 0.197
Weiss et al. (PMID: 28513610) report on 8 individuals (from 6 unrelated families) with heterozygous pathogenic variants affecting ZNF462.
Frequent features included ptosis metopic ridging, craniosynostosis, dysgenesis of corpus callosum. DD (with or without ASD) was a feature in 4 (4/8), one of whom was reported to present mild ID.
4 LoF mutations as well as 2 9q31.2 deletions spanning also other genes are reported [NM_021224.4]:
Fam. 1 - c.3787C>T p.(Arg1263*) (familial) - Normal development in all 3 family members
Fam. 2 - c.2979_2980delinsA p.(Val994Trpfs*147) (de novo) - DD
Fam. 3 - c.4263delA p.(Glu1422Serfs*6) (de novo) - DD
Fam. 4 - Chr9:g.(108940763-110561397)del (hg19) (de novo) - Normal development
Fam. 5- Chr9:g(108464368-110362345)del (hg19) (de novo) - DD with mild ID
Fam. 6 - c.5145delC p.(Tyr1716Thrfs*28) (de novo) - DD
There were no expression/functional studies performed although haploinsufficiency can be presumed based on these variants (ZNF462 has a pLI of 1 in ExAC).
Cosemans et al. (PMID: 29427787) report on an individual investigated - among others - for mild ID and ASD. This individual harbored a de novo (complex) translocation disrupting ZNF462 and KLF12.
As this subject presented similar features to those reported by Weiss et al. (eg. craniofacial anomalies, abn. development, ASD) and given that KLF12 is not associated with any disorder, the phenotype of this individual was thought to be secondary to disruption of ZNF462.
Details on this patient - before delineation of the translocation breakpoints - were provided previously by Fryns and Hendrickx ( PMID:9297446).
Cited by the previous article, a further case of ZNF462 disruption due to translocation was previously published in the literature (same individual - Talisetti et al. PMID: 14564155 / Ramocki et al. PMID: 12825074). Profound ID was among the features of this individual although the translocation disrupted also a further ID gene (ASXL2).
In ClinVar 8 variants have been submitted as pathogenic/likely pathogenic although a phenotype is provided only for 3 variants published by Weiss et al.(submitting lab participating in PMID: 28513610 / SCV000494060.1 corresp. to Fam.1 / SCV000494061.1 - Fam.2 / SCV000494062.1 - Fam. 3).
Several individuals with de novo coding variants in ZNF462 have been reported in the context of larger cohorts (some with ID as a principal feature).
In Decipher apart from the DDD study participants DDD4K.03663 and DDD4K.03792 (appearing in the denovo-db) with LoF and abnormality of the nervous system, several further individuals have been submitted.
2 of these subjects, harbored a de novo LoF variant (submitted as pathogenic) and had ID as a feature [DECIPHER IDs: 273587 and 270154].
ZNF462 is included in the DD panel of G2P, associated with Craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay [Disease confidence: probable / Global DD (but not ID) among the phenotypes assigned to this entry].
This gene is not associated with any phenotype in OMIM.
ZNF462 is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
As a result this gene can be considered for inclusion in the ID panel probably as amber (or green if the current evidence is thought to be sufficient).
Sources: Literature, Radboud University Medical Center, Nijmegen
Created: 2 Jan 2019, 12:12 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ptosis; Prominent metopic ridge; Craniosynostosis; Global developmental delay; Intellectual disability; Autistic behavior
Variants in this GENE are reported as part of current diagnostic practice
Source Expert Review Green was added to ZNF462. Source Expert Review was added to ZNF462. Added phenotypes Ptosis, Prominent metopic ridge, Craniosynostosis, Global developmental delay, Intellectual disability, Autistic behavior for gene: ZNF462 Publications for gene ZNF462 were changed from 28513610; 29427787; 14564155; 12825074 to 28513610; 12825074; 29427787; 14564155 Rating Changed from No List (delete) to Green List (high evidence)
gene: ZNF462 was added gene: ZNF462 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: ZNF462 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZNF462 were set to 28513610; 29427787; 14564155; 12825074 Phenotypes for gene: ZNF462 were set to Ptosis; Prominent metopic ridge; Craniosynostosis; Global developmental delay; Intellectual disability; Autistic behavior Penetrance for gene: ZNF462 were set to unknown Review for gene: ZNF462 was set to AMBER gene: ZNF462 was marked as current diagnostic