%0 Journal Article
%T Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia.
%A Asif M
%A Khayyat AIA
%A Alawbathani S
%A Abdullah U
%A Sanner A
%A Georgomanolis T
%A Haasters J
%A Becker K
%A Budde B
%A Becker C
%A Thiele H
%A Baig SM
%A Isidoro-García M
%A Winter D
%A Pogoda HM
%A Muhammad S
%A Hammerschmidt M
%A Kraft F
%A Kurth I
%A Martin HG
%A Wagner M
%A Nürnberg P
%A Hussain MS
%J Genet Med
%V 26
%N 7
%D 2024 Jul 16
%M 38641995
%F 8.864
%R 10.1016/j.gim.2024.101143
%X <B>OBJECTIVE: </B>Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.