{Reference Type}: Journal Article
{Title}: Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia.
{Author}: Asif M;Khayyat AIA;Alawbathani S;Abdullah U;Sanner A;Georgomanolis T;Haasters J;Becker K;Budde B;Becker C;Thiele H;Baig SM;Isidoro-García M;Winter D;Pogoda HM;Muhammad S;Hammerschmidt M;Kraft F;Kurth I;Martin HG;Wagner M;Nürnberg P;Hussain MS;
{Journal}: Genet Med
{Volume}: 26
{Issue}: 7
{Year}: 2024 Jul 16
{Factor}: 8.864
{DOI}: 10.1016/j.gim.2024.101143
{Abstract}: <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.