A novel missense variant in ZC4H2, c.196C&gt;T p.(Leu66Phe), is associated with a mild, ZC4H2-related X-linked syndromic intellectual disability (ZARD) phenotype

Garg, Ria; Zhang, Wenying; Hartman, Julianne; Slavotinek, Anne

doi:10.3389/fped.2025.1518782

CASE REPORT article

Front. Pediatr.

Sec. Genetics of Common and Rare Diseases

Volume 13 - 2025 | doi: 10.3389/fped.2025.1518782

A novel missense variant in ZC4H2, c.196C>T p.(Leu66Phe), is associated with a mild, ZC4H2-related X-linked syndromic intellectual disability (ZARD) phenotype

Provisionally accepted

Ria Garg ^1*

Wenying Zhang ²

Julianne Hartman ²

Anne Slavotinek ²

¹ Upstate Medical University, Syracuse, United States
² Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States

The final, formatted version of the article will be published soon.

ZC4H2 is an X-linked gene that has emerged as critical for neural development, synaptic functioning, and gene regulation. We present an 11-month-old male who was evaluated for bilateral congenital vertical talus identified in the newborn period. Exome sequencing identified a hemizygous, missense variant in ZC4H2, NM_018684.4:c.196C>T p.(Leu66Phe), that affects the same amino acid residue as a previously reported, pathogenic ZC4H2 variant, c.197T>A p.(Leu66His). The variant was inherited from his mother, who had camptodactyly of the fifth fingers, and was also present in the maternal uncle who carried a diagnosis of cerebral palsy. The pathogenic missense variant in this family is located in the coiled-coil domain of the ZC4H2 protein. Although data remains scarce, missense variants in this domain may be associated with a milder, ZC4H2-Associated Rare Disorder (ZARD) phenotype.

Keywords: Contracture, Neurodevelopmental disorders, Growth and Development, ZC4H2, ZARD

Received: 28 Oct 2024; Accepted: 17 Mar 2025.

Copyright: © 2025 Garg, Zhang, Hartman and Slavotinek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Ria Garg, Upstate Medical University, Syracuse, United States

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