Genetic epilepsy syndromesGene: ZNF142
As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Sufficient cases for inclusion. Promoted from Amber to Green.
Created: 25 Nov 2019, 8:22 p.m. | Last Modified: 25 Nov 2019, 8:22 p.m.
Panel Version: 1.427
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
AR NEDISHM. Khan et al, 2019 (31036918) - 7 patients from 4 unrelated familes, 2 were consanguineous (1 Turkish, 1 Pakistani). 5 patients had seizures as part of their phenotype. Of these 2 had only 1 general tonic-clonic seizure around the age of 1-2 (1 sibling from famly A and Family B). The other 3 had earlier onset tonic-clonic seizures which tended to abate or respond to medication (Family C), they also had an affected older sibling with a similar phenptype who had long lasting seizures and was deceased - no DNA available to test. Likely pathogenic variants detected- 3 cases had nonsense or fs variants and 1 case had missense changes predicted to be damaging to protein function.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
No epilepsy phenotype listed on HGMDPro, OMIM phenotype #618425 (NEURODEVELOPMENTAL DISORDER WITH IMPAIRED SPEECH AND HYPERKINETIC MOVEMENTS) details that some patients may develop seizures quoting Khan et al PMID: 31036918, previously commented on in reviews below.
Created: 23 Aug 2019, 10:25 a.m. | Last Modified: 23 Aug 2019, 10:25 a.m.
Panel Version: 1.256
NEURODEVELOPMENTAL DISORDER WITH IMPAIRED SPEECH AND HYPERKINETIC MOVEMENTS
Expert review by Konstantinos Varvagiannis based on Khan et al. (2019 - PMID: 31036918).
This paper reports on 4 independent families with 7 affected individuals, who have biallelic mutations in ZNF142, 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.
Seizures are not a consistent phenotype reported:
Family 1, one sibling had seizures on more than one occasion but little information is reported, the other sibling was reported to not be affected.
Family 2 a seizure was reported only once but there was no evidence of epileptiform discharges.
Family 3, one individual had 7-8 seizures in the first 3 years of life and abated with no medical intervention. For the dizygotic twins in family 3 one twin had seizures 7-8 times in her life, the other sibling experiences seizures at variable frequency from twice a week to 7-8 times a day.
Family 4, the individual did not experience any seizures.
Therefore ZNF142 should be classified as Amber and await for more evidence, to see if epilepsy is more consistent within the phenotype.
Created: 8 Jul 2019, 2:41 p.m. | Last Modified: 8 Jul 2019, 2:49 p.m.
Panel Version: 0.62
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 amber (seizures in 5/7 individuals, though many had a single occurrence) or green.
Created: 1 May 2019, 9:45 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia
Gene: znf142 has been classified as Green List (High Evidence).
Source Wessex and West Midlands GLH was added to ZNF142.
Source NHS GMS was added to ZNF142.
Source Expert Review was added to ZNF142. Source Expert Review Amber 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 Amber List (moderate evidence)
gene: ZNF142 was added gene: ZNF142 was added to Genetic epilepsy syndromes. 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 Incomplete Review for gene: ZNF142 was set to AMBER