ZC4H2 – Female-restricted Wieacker-Wolff Syndrome

ZC4H2 on the X chromosome is associated with Female-restricted Wieacker-Wolff syndrome, an X-linked neurodevelopmental disorder characterized in heterozygous females by severe arthrogryposis multiplex congenita and Pierre-Robin sequence. Two unrelated female probands have been reported with de novo loss-of-function nonsense variants—c.199C>T (p.Arg67Ter) and c.352C>T (p.Gln118Ter)—each presenting with classic features and no family history of the disorder (2 probands) (PMID:31885220, PMID:36140726). No segregating affected relatives have been described.

Functional studies of the c.352C>T (p.Gln118Ter) variant demonstrate absent ZC4H2 protein in 293T cells and impaired oxidative phosphorylation and growth in iPSC-derived neural stem cells, consistent with a loss-of-function mechanism (PMID:36140726). These data provide moderate experimental support for pathogenicity. No conflicting evidence has been reported.

Key Take-home: Heterozygous de novo ZC4H2 nonsense variants causing protein loss-of-function underlie Female-restricted Wieacker-Wolff syndrome, supporting molecular diagnosis and potential development of targeted therapies.

References

• Genes • 2022 • Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the ZC4H2 Gene PMID:36140726
• Molecular Genetics & Genomic Medicine • 2020 • A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome PMID:31885220

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