Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia

Authors

Maria Asif, University of Cologne,Germany
Arwa Khayyat Ishaq A Khayyat, King Saud University, Saudi Arabia
Salem Alawbathani, University of Cologne,Germany
Uzma Abdullah, Arid Agriculture University,Pakistan
Anne Sanner, University of Bonn,Germany
Theodoros Georgomanolis, University of Cologne,Germany
Judith Haasters, University of Munich,Germany
Kerstin Becker, University of Cologne,Germany
Shahid Mahmood Baig, Aga Khan UniversityFollow
Maria Isidoro García, University of glance,Spain

Document Type

Article

Department

Biological and Biomedical Sciences

Abstract

Purpose: Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive.
Methods: We studied five affected individuals from three unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We employed exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing.
Results: We identified biallelic variants in ZFTRAF1, encoding a protein of yet unknown function. Four affected individuals from two unrelated families segregated two homozygous frameshift variants in ZFTRAF1, whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of two affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process.
Conclusion: Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.

Comments

Volume, issue and pagination are not provided by author/publisher.

Publication (Name of Journal)

Genetics in Medicine

DOI

10.1016/j.gim.2024.101143

Recommended Citation

Asif, M., Khayyat, A. I., Alawbathani, S., Abdullah, U., Sanner, A., Georgomanolis, T., Haasters, J., Becker, K., Baig, S. M., García, M. I. (2024). Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia. Genetics in Medicine.
Available at: https://ecommons.aku.edu/pakistan_fhs_mc_bbs/1047