Variants in PUS7 cause intellectual disability with speech delay, microcephaly, short stature, and aggressive behavior

We describe six patients from three families with three homozygous protein truncating variants in PUS7: c.89_90del, p.(Thr30Lysfs20*); c.1348C>T, p.(Arg450*); and a deletion of the penultimate exon 15. All patients have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, Pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity with slower walking speed and disorientation supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function. Mapping of pseudouridylation in WT versus pus7 mutants in drosophila samples.