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Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia. 2024
Maria Asif, and
Arwa Ishaq A Khayyat, and
Salem Alawbathani, and
Uzma Abdullah, and
Anne Sanner, and
Theodoros Georgomanolis, and
Judith Haasters, and
Kerstin Becker, and
Birgit Budde, and
Christian Becker, and
Holger Thiele, and
Shahid M Baig, and
María Isidoro-García, and
Dominic Winter, and
Hans-Martin Pogoda, and
Sajjad Muhammad, and
Matthias Hammerschmidt, and
Florian Kraft, and
Ingo Kurth, and
Hilario Gomez Martin, and
Matias Wagner, and
Peter Nürnberg, and
Muhammad Sajid Hussain
Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
OBJECTIVE 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. CONCLUSIONS Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.
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