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

Maria Asif, Arwa Ishaq A. Khayyat, Salem Alawbathani, Uzma Abdullah, Anne Sanner, Theodoros Georgomanolis, Judith Haasters, Kerstin Becker, Birgit Budde, Christian Becker, Holger Thiele, Shahid M. Baig, María Isidoro-García, Dominic Winter, Hans Martin Pogoda, Sajjad Muhammad, Matthias Hammerschmidt, Florian Kraft, Ingo Kurth, Hilario Gomez MartinMatias Wagner, Peter Nürnberg, Muhammad Sajid Hussain

Research output: Contribution to journalArticlepeer-review


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 5 affected individuals from 3 unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We used 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 2 unrelated families segregated 2 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 2 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.

Original languageEnglish
Article number101143
JournalGenetics in Medicine
Issue number7
Publication statusPublished - Jul 2024


  • Autophagy
  • CYHR1
  • mRNA processing
  • Neurodevelopmental disorders


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