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. 2024 Sep:158:100-112.
doi: 10.1016/j.pediatrneurol.2024.06.009. Epub 2024 Jun 24.

Genotype-Phenotype Correlations and Sex Differences in ZC4H2-Associated Rare Disorder

Sydney Peters  1 , Kristen Sportiello  2 , Shreya Mandalapu  3 , Ashlie Nguyen  4 , Ryan Carrier  5 , Carolyn Dickinson  5 , Alex Paciorkowski  5 , David Bearden  5
Affiliations

Genotype-Phenotype Correlations and Sex Differences in ZC4H2-Associated Rare Disorder

Sydney Peters et al. Pediatr Neurol. 2024 Sep.

Abstract

Background: ZC4H2-associated rare disorder (ZARD) is caused by pathogenic variations in the ZC4H2 gene on the X chromosome. This gene codes for a zinc finger protein involved in neural development. ZARD is characterized by highly variable symptoms, potentially influenced by the sex of the individual.

Methods: The ZC4H2-Associated Rare Disorder Natural History Study is a prospective natural history study conducted among individuals with ZARD that consists of standardized interviews, developmental assessments, and neurological examinations conducted every six months for two years. In this article, we present data from baseline visits with 40 participants, the largest ZARD cohort studied thus far, focusing on genotype-phenotype correlations and sex differences. Fisher exact, maximum likelihood χ2, and Mann-Whitney tests were utilized.

Results: Males tended to have maternally inherited ZC4H2 pathogenic variations, whereas females tended to have de novo variations (P < 0.001). Female participants were more likely to have contractures at birth (P < 0.01), arthrogryposis multiplex congenita (P < 0.001), spasticity on examination (P < 0.1), and lower limb muscle atrophy (P < 0.05). Male participants were more likely to have seizures (P < 0.1), intermittent pain (P < 0.01), severe vision impairment (P < 0.05), dysphagia for solids (P < 0.01), and generalized muscle atrophy (P < 0.05).

Conclusions: Our study suggests there is significant overlap in severity and range of symptoms between males and females, although several symptoms are more common in one sex than the other. Further analysis is needed to better understand how pathogenic variation type affects phenotype.

Keywords: Arthrogryposis; Genetic disorder; Natural history; ZARD; ZC4H2.

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Conflict of interest statement

Declaration of competing interest An immediate family member of Ms. Sportiello has received research support from the National Institutes of Health and personal compensation in the range of $50,000 to $99,999 for serving as a Research Assistant with the National Institutes of Health. Dr. Carrier has received personal compensation in the range of $500 to $4,999 for serving as a Project Stakeholder with TANGO2 Research Foundation. Dr. Paciorkowski has received research support from the University of Rochester. Dr. Bearden has received personal compensation in the range of $500 to $4999 for serving as a Consultant for Biogen and personal compensation in the range of $500 to $4999 for serving as a Consultant for Praxis. Dr. Bearden has also served as a consultant for Atalanta, Servier, and UCB pharmaceutical companies. Dr. Bearden has also received personal compensation in the range of $100,000 to $499,999 for serving as an Expert Witness for law firms. Other authors have no declarations of interest.

Figures

Figure 1.
Figure 1.
ZC4H2 Model# with Locations of Participants’ Pathogenic Variations # Model from AlphaFold protein structure database: https://alphafold.ebi.ac.uk/entry/Q9NQZ6. No changes were made to the model. AlphaFold Data Copyright (2022) DeepMind Technologies Limited. * Corresponds to two participants who are siblings ** Corresponds to two participants who are not siblings
Figure 1.
Figure 1.
ZC4H2 Model# with Locations of Participants’ Pathogenic Variations # Model from AlphaFold protein structure database: https://alphafold.ebi.ac.uk/entry/Q9NQZ6. No changes were made to the model. AlphaFold Data Copyright (2022) DeepMind Technologies Limited. * Corresponds to two participants who are siblings ** Corresponds to two participants who are not siblings
Figure 1.
Figure 1.
ZC4H2 Model# with Locations of Participants’ Pathogenic Variations # Model from AlphaFold protein structure database: https://alphafold.ebi.ac.uk/entry/Q9NQZ6. No changes were made to the model. AlphaFold Data Copyright (2022) DeepMind Technologies Limited. * Corresponds to two participants who are siblings ** Corresponds to two participants who are not siblings
See this image and copyright information in PMC

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