{Reference Type}: Journal Article
{Title}: Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.
{Author}: Salpietro V;Maroofian R;Zaki MS;Wangen J;Ciolfi A;Barresi S;Efthymiou S;Lamaze A;Aughey GN;Al Mutairi F;Rad A;Rocca C;Calì E;Accogli A;Zara F;Striano P;Mojarrad M;Tariq H;Giacopuzzi E;Taylor JC;Oprea G;Skrahina V;Rehman KU;Abd Elmaksoud M;Bassiony M;El Said HG;Abdel-Hamid MS;Al Shalan M;Seo G;Kim S;Lee H;Khang R;Issa MY;Elbendary HM;Rafat K;Marinakis NM;Traeger-Synodinos J;Ververi A;Sourmpi M;Eslahi A;Khadivi Zand F;Beiraghi Toosi M;Babaei M;Jackson A; ;Bertoli-Avella A;Pagnamenta AT;Niceta M;Battini R;Corsello A;Leoni C;Chiarelli F;Dallapiccola B;Faqeih EA;Tallur KK;Alfadhel M;Alobeid E;Maddirevula S;Mankad K;Banka S;Ghayoor-Karimiani E;Tartaglia M;Chung WK;Green R;Alkuraya FS;Jepson JEC;Houlden H;
{Journal}: Am J Hum Genet
{Volume}: 111
{Issue}: 1
{Year}: 2024 01 4
{Factor}: 11.043
{DOI}: 10.1016/j.ajhg.2023.11.012
{Abstract}: The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.