PUBLICATION
Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: a novel hypomorphic variant and high prevalence of tethered cord
- Authors
- Wongkittichote, P., Choi, T.I., Kim, O.H., Riley, K., Koeberl, D., Narayanan, V., Ramsey, K., Balak, C., Schwartz, C., Cueto-Gonzalez, A.M., Munell Casadesus, F., Kim, C.H., Shinawi, M.S.
- ID
- ZDB-PUB-221018-98
- Date
- 2022
- Source
- Clinical genetics 103(2): 167-178 (Journal)
- Registered Authors
- Kim, Cheol-Hee
- Keywords
- Tethered cord, Wieacker-Wolff syndrome, X-linked disorder, ZC4H2-related disorder, arthrogryposis, zebrafish model
- MeSH Terms
-
- Alleles
- Animals
- Female
- Genetic Diseases, X-Linked*/genetics
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Male
- Nerve Tissue Proteins/genetics
- Neural Tube Defects*/genetics
- Nuclear Proteins/genetics
- Phenotype
- Prevalence
- Zebrafish*/genetics
- PubMed
- 36250278 Full text @ Clin. Genet.
Citation
Wongkittichote, P., Choi, T.I., Kim, O.H., Riley, K., Koeberl, D., Narayanan, V., Ramsey, K., Balak, C., Schwartz, C., Cueto-Gonzalez, A.M., Munell Casadesus, F., Kim, C.H., Shinawi, M.S. (2022) Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: a novel hypomorphic variant and high prevalence of tethered cord. Clinical genetics. 103(2):167-178.
Abstract
ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associated with Wieacker-Wolff syndrome (MIM# 314580), an X-linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish zc4h2 null mutants recapitulated the human phenotype, showed complete loss of vsx2 expression in brain, and exhibited abnormal swimming and balance problems. Here we report 7 new patients (4 males and 3 females) with ZC4H2-related disorder from 6 unrelated families. Four of the 6 ZC4H2 variants are novel: three missense variants, designated as c.142T>A (p.Tyr48Asn), c.558G>A (p.Met186Ile) and c.602C>T (p.Pro201Leu), and a nonsense variant, c.618C>A (p.Cys206*). Two previously reported variants: a nonsense variant c.199C>T (p.Arg67*) and a splice site variant (c.225+5G>A). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under-recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human ZC4H2 wild-type or variant mRNAs into zc4h2 null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue vsx2 expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with ZC4H2-related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of ZC4H2 variants.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping