HGNC Approved Gene Symbol: ZNF142
Cytogenetic location: 2q35 Genomic coordinates (GRCh38) : 2:218,633,329-218,659,623 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | Neurodevelopmental disorder with impaired speech and hyperkinetic movements | 618425 | Autosomal recessive | 3 |
Transcriptional regulatory proteins containing tandemly repeated zinc finger domains are thought to be involved in both normal and abnormal cellular proliferation and differentiation. One abundant class of such transcriptional regulators resembles the Drosophila Kruppel segmentation gene product due to the presence of repeated Cys2-His2 (C2H2) zinc finger domains that are connected by conserved sequences, called H/C links. See ZNF91 (603971) for general information on zinc finger proteins (summary by Tommerup et al., 1993).
By screening a human insulinoma cDNA library with a degenerate oligonucleotide corresponding to the H/C linker sequence, Tommerup et al. (1993) isolated cDNAs potentially encoding zinc finger proteins. Tommerup and Vissing (1995) performed sequence analysis on a number of these cDNAs and identified several novel zinc finger protein genes, including ZNF142. The ZNF142 cDNA predicts a protein belonging to the Kruppel family of zinc finger proteins.
By sequencing random cDNAs corresponding to relatively long transcripts, Nagase et al. (1996) identified a cDNA encoding ZNF142, which they called KIAA0236. The deduced ZNF142 protein has 1,687 amino acids. Northern blot analysis detected ZNF142 expression in all 16 human tissues examined.
Using a radiation hybrid mapping panel, Nagase et al. (1996) mapped the ZNF142 gene to chromosome 2. By FISH, Tommerup and Vissing (1995) mapped the ZNF142 gene to 2q34-q35.
In 7 patients from 4 unrelated families with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425), Khan et al. (2019) identified homozygous or compound heterozygous mutations in the ZNF142 gene (604083.0001-604083.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Four of the 6 mutations identified were frameshift or nonsense, consistent with a loss of function. Functional studies of the variants and studies of patient cells were not performed, although Khan et al. (2019) noted that mutations in similar zinc finger family genes have been identified in patients with neurodevelopmental disorders.
Kamal et al. (2022) identified compound heterozygous mutations (Q9X, 604083.0007 and R581C, 604083.0008) in the ZNF142 gene in a 5-year-old boy, born of consanguineous Iranian parents, with NEDISHM. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing.
In 35 patients (9 previously reported) from 21 unrelated families (5 previously reported) segregating NEDISHM, Christensen et al. (2022) identified biallelic mutations in the ZNF142 gene, including 27 different mutations, 18 of which were novel. Twenty-one patients had a homozygous mutation and 14 patients had compound heterozygous mutations. One patient (individual 23) had a homozygous single nucleotide deletion due to maternal uniparental disomy of an 8.5-kb region including the ZNF142 gene. Twenty-three of the mutations were predicted to result in a truncated protein and 4 were missense mutations. Three of the missense mutations (C1233F, F1295L, and R1500W) were located in the conserved zinc finger motifs, and 1 mutation (S763C) was located in an unstructured region. The 3 patients who had compound heterozygosity for 1 or 2 missense mutations had a somewhat milder phenotype compared to those with 2 truncating mutations.
In 2 females from closely related consanguineous Bedouin families with NEDISHM, Proskorovski-Ohayon et al. (2024) identified a homozygous mutation in the ZNF142 gene (c.4002delG; 604083.0009) that was predicted to result in a frameshift and premature termination. Functional studies in patient cells were not performed.
Proskorovski-Ohayon et al. (2024) used CRISPR editing to generate a mouse model with homozygosity for an R1508X mutation in the zfp142 gene. Mutant mice had features of hyperactivity and anxiety, which were primarily seen in female mutant mice. There was significant depletion of lymphoid and hematopoietic cells in the bone marrow and spleens of the mutant mice, which was more severe in females compared to males. Brains of the mutant mice had normal anatomic and histologic brain structures. Transcriptome analysis of cerebellar, cortex, and hippocampal tissue demonstrated downregulation of Taok1 (610266) expression in the cortex and Mllt6 (600328) in the hippocampus of female mutant mice compared to female controls.
In 2 adult sisters, born of unrelated parents of Slovakian descent (family A), with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425), Khan et al. (2019) identified compound heterozygous mutations in the ZNF142 gene: a 1-bp deletion (c.1292delG, NM_001105537.2) in exon 7, predicted to result in a frameshift and premature termination (Cys431LysfsTer11), and a 2-bp deletion in exon 6 (c.817_818delAA; 604083.0002), predicted to result in a frameshift and premature termination (Lys273GlufsTer32). Both mutations were predicted to result in nonsense-mediated mRNA decay and a complete loss of function, although functional studies of the variants and studies of patient cells were not performed. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. They were not found in the ExAC or gnomAD databases or in an in-house control exome database of 10,000 individuals.
For discussion of the 2-bp deletion (c.817_818delAA, NM_001105537.2) in exon 6 of the ZNF142 gene, predicted to result in a frameshift and premature termination (Lys273GlufsTer32), that was found in compound heterozygous state in 2 sisters with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425) by Khan et al. (2019), see 604083.0001.
In an 8-year-old girl, born of consanguineous Turkish parents (family B), with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425), Khan et al. (2019) identified a homozygous c.3175C-T transition (c.3175C-T, NM_001105537.2) in exon 8 of the ZNF142 gene, resulting in an arg1059-to-ter (R1059X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found twice in heterozygous state in the gnomAD database (frequency of 8.022 x 10(-6)). Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to truncate the latter half of the protein. The patient also carried homozygous variants in other genes, which were not thought to contribute to the phenotype.
In 3 sisters, including a pair of dizygotic twins, born of consanguineous Pakistani parents (family C), with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425), Khan et al. (2019) identified a homozygous complex mutation in exon 8 of the ZNF142 gene. The variants occurred in cis: a 1-bp deletion (c.4183delC, NM_001105537.2), predicted to result in a frameshift and premature termination (Leu1395TrpfsTer2), and a c.4185G-A transition (c.4185G-A, NM_001105537.2), which was a synonymous variant. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither change was present in homozygous state in the gnomAD database, but each was found once in heterozygous state. The 1-bp deletion was predicted to truncate 292 amino acids from the C-terminal encoding region of the protein. Functional studies of the variant and studies of patient cells were not performed, but the frameshift mutation was predicted to be pathogenic.
In a 10-year-old girl, born of unrelated parents (family D), with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425) Khan et al. (2019) identified compound heterozygous missense mutations in the ZNF142 gene: a c.3698G-T transversion (c.3698G-T, NM_001105537.2) in exon 8, resulting in a cys1233-to-phe (C1233F) substitution, and a c.4498C-T transition in exon 9, resulting in an arg1500-to-trp (R1500W; 604083.0006) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Each was found at a low frequency in the gnomAD database. The mutations occurred at highly conserved residues in C2H2-type zinc finger domains. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.4498C-T transition (c.4498C-T, NM_001105537.2) in exon 9 of the ZNF142 gene, resulting in an arg1500-to-trp (R1500W) substitution, that was found in compound heterozygous state in 2 sisters with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425) by Khan et al. (2019), see 604083.0005.
In a 5-year-old boy, born of consanguineous Iranian parents, with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425), Kamal et al. (2022) identified compound heterozygosity for 2 mutations in the ZNF142 gene, a c.25C-T transition (c.25C-T, NM_001105537) in exon 4, resulting in a gln9-to-ter (Q9X) substitution, and a c.1741C-T transition in exon 6, resulting in an arg581-to-cys (R581C; 604083.0008) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were present in heterozygous state in the parents. The minor allele frequency for the Q9X mutation in the gnomAD database was 0.000467 and the minor allele frequency for the R581C mutation was 0.00000801. Functional studies were not performed.
For discussion of the c.1741C-T transition (c.1741C-T, NM_001105537) in exon 6 of the ZNF142 gene, resulting in an arg581-to-cys (R581C) substitution, that was identified in compound heterozygous state in a patient with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425) by Kamal et al. (2022), see 604083.0007.
In 2 females from a consanguineous Bedouin family with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM; 618425), Proskorovski-Ohayon et al. (2024) identified homozygosity for a 1-bp deletion (c.4002delG, NM_001105537.4) in the ZNF142 gene, predicted to result in a frameshift and premature termination (Leu1335fsTer62). The mutation, which was identified by homozygosity mapping, whole-exome sequencing, and Sanger sequencing, segregated with the disorder in the family.
Christensen, M. B., Levy, A. M., Mohammadi, N. A., Niceta, M., Kaiyrzhanov, R., Dentici, M. L., Al Alam, C., Alesi, V., Benoit, V., Bhatia, K. P., Bierhals, T., Bosselmann, C. M., and 45 others. Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder. Clin. Genet. 102: 98-109, 2022. [PubMed: 35616059] [Full Text: https://doi.org/10.1111/cge.14165]
Kamal, N., Khamirani, H. J., Mohammadi, S., Dastgheib, S. A., Dianatpour, M., Tabei, S. M. B. ZNF142 mutation causes neurodevelopmental disorder with speech impairment and seizures: novel variants and literature review. Europ. J. Med. Genet. 65: 104522, 2022. [PubMed: 35618198] [Full Text: https://doi.org/10.1016/j.ejmg.2022.104522]
Khan, K., Zech, M., Morgan, A. T., Amor, D. J., Skorvanik, M., Khan, T. N., Hildebrand, M. S., Jackson, V. E., Scerri, T. S., Coleman, M., Rigby, K. A., Scheffer, I. E., and 18 others. Recessive variants in ZNF142 cause a complex neurodevelopmental disorder with intellectual disability, speech impairment, seizures, and dystonia. Genet. Med. 21: 2532-2542, 2019. [PubMed: 31036918] [Full Text: https://doi.org/10.1038/s41436-019-0523-0]
Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res. 3: 321-329, 1996. [PubMed: 9039502] [Full Text: https://doi.org/10.1093/dnares/3.5.321]
Proskorovski-Ohayon, R., Eskin-Schwartz, M., Shorer, Z., Kadir, R., Halperin, D., Drabkin, M., Yogev, Y., Aharoni, S., Hadar, N., Cohen, H., Eremenko, E., Perez, Y., Birk, O. S. ZNF142 mutation causes sex-dependent neurologic disorder. J. Med. Genet. 61: 566-577, 2024. [PubMed: 38296634] [Full Text: https://doi.org/10.1136/jmg-2023-109447]
Tommerup, N., Aagaard, L., Lund, C. L., Boel, E., Baxendale, S., Bates, G. P., Lehrach, H., Vissing, H. A zinc-finger gene ZNF141 mapping at 4p16.3/D4S90 is a candidate gene for the Wolf-Hirschhorn (4p-) syndrome. Hum. Molec. Genet. 2: 1571-1575, 1993. [PubMed: 8268908] [Full Text: https://doi.org/10.1093/hmg/2.10.1571]
Tommerup, N., Vissing, H. Isolation and fine mapping of 16 novel human zinc finger-encoding cDNAs identify putative candidate genes for developmental and malignant disorders. Genomics 27: 259-264, 1995. [PubMed: 7557990] [Full Text: https://doi.org/10.1006/geno.1995.1040]