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Intellectual disability

Gene: ZNF142

Green List (high evidence)

ZNF142 (zinc finger protein 142)
EnsemblGeneIds (GRCh38): ENSG00000115568
EnsemblGeneIds (GRCh37): ENSG00000115568
OMIM: 604083, Gene2Phenotype
ZNF142 is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Expert review by Konstantinos Varvagiannis based on Khan et al. (2019 - PMID: 31036918).

This paper reports on 4 independent families with 7 affected individuals, this is the first time gene disease association for ZNF142 has been reported upon. ZNF142 is in OMIM and based on this paper only, it is not in Gene2Phenotype.

Sequencing data was available for all reported individuals but not for all family members, in family B only the individual was reported upon and only the mother in Family C, but inheritance shows as homozygous.
The proband in Family D, is boderline for ID, however all other individuals except one, who is moderate, have severe ID. Therefore there is enough evidence with (>3) from independent unrelated individuals to classify ZNF142 as Green gene on the ID panel.
Created: 23 May 2019, 2:44 p.m. | Last Modified: 22 Jul 2019, 9:42 a.m.
Panel Version: 0.205

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Khan et al. (2019 - PMID: 31036918) describe the phenotype of 7 females from 4 families, harboring biallelic likely pathogenic ZNF142 variants.

Overlapping features included cognitive impairment (ID in 6/7 from 3 families, borderline intellectual functioning was reported one occasion), speech impairement and motor impairment (7/7), and variably penetrant seizures (5/7), tremor (4/7) and dystonia (3/7). Most individuals (5/7) had experienced at least one episode of seizures (tonic-clonic) though seizures were recurrent in 3 sibs.

Other disorders with ID (eg. Angelman syndrome, Rett syndrome, chromosomal disorders) or movement disorders as a feature were previously ruled out for many subjects.

6 individuals were homozygous or compound heterozygous for LoF (stopgain or frameshift) variants. One individual harbored 2 missense SNVs in the compound heterozygous state. Variants reported include (NM_001105537.2): c. 817_818delAA (p.Lys273Glufs*32), c.1292delG (p.Cys431Leufs*11), c.3175C>T (p.Arg1059*), c.4183delC (p.Leu1395*), c.3698G>T (p.Cys1233Phe), c.4498C>T (p.Arg1500Trp) with the LoF variants predicted to result in NMD. Expression or functional studies were not carried out.

ZNF142 encodes a C2H2 domain-containing transcription factor. Mutations in other zinc finger proteins (ZNF/zfp) have been reported in several neurodevelopmental disorders impacting the CNS (eg. ZBTB20 and ZBTB11 heterozygous and biallelic mutations, respectively) and/or presenting with movement disorders among their manifestations (eg. YY1).

As the authors comment, homozygous ablation of the orthologous (Zfp142) locus in mice results in behavioral and neurological phenotypes [MGI ref.ID: J:211773 cited - http://www.informatics.jax.org/marker/reference/J:211773 (though Zfp142 or its locus do not seem to appear in the list)].

ZNF142 is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories. It is not associated with any phenotype in OMIM, nor in G2P.

As a result, this gene can be considered for inclusion in the current panel as probably as green (individuals from 3 families, appropriate degree of ID for the current panel) or amber (if further evidence would be required).
Sources: Literature
Created: 1 May 2019, 9:42 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
  • Expert Review Green
  • Expert Review
Phenotypes
  • Seizures
  • Dystonia
  • Intellectual disability
  • Global developmental delay
  • Tremor
  • Neurodevelopmental disorder with impaired speech and hyperkinetic movements, 618425
OMIM
604083
Clinvar variants
Variants in ZNF142
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to ZNF142. Source Expert Review was added to ZNF142. Added phenotypes Neurodevelopmental disorder with impaired speech and hyperkinetic movements, 618425 for gene: ZNF142 Rating Changed from No List (delete) to Green List (high evidence)

1 May 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: ZNF142 was added gene: ZNF142 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ZNF142 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF142 were set to 31036918 Phenotypes for gene: ZNF142 were set to Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia Penetrance for gene: ZNF142 were set to unknown Review for gene: ZNF142 was set to GREEN