De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome
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ORIGINAL INVESTIGATION
De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome Roser Ufartes1 · Hanna Berger2 · Katharina Till2 · Gabriela Salinas3 · Marc Sturm4 · Janine Altmüller5 · Peter Nürnberg5,6 · Holger Thiele5 · Rudolf Funke7 · Neophytos Apeshiotis8 · Hendrik Langen9 · Bernd Wollnik1,10 · Annette Borchers2,11 · Silke Pauli1 Received: 18 February 2020 / Accepted: 2 May 2020 © The Author(s) 2020
Abstract We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome (AUTS2 syndrome). We determined human FBRSL1 transcripts and describe proteincoding forms by Western blot analysis as well as the cellular localization by immunocytochemistry stainings. All detected mutations affect the two short N-terminal isoforms, which show a ubiquitous expression in fetal tissues. Next, we performed a Fbrsl1 knockdown in Xenopus laevis embryos to explore the role of Fbrsl1 during development and detected craniofacial abnormalities and a disturbance in neurite outgrowth. The aberrant phenotype in Xenopus laevis embryos could be rescued with a human N-terminal isoform, while the long isoform and the N-terminal isoform containing the mutation p.Gln163* isolated from a patient could not rescue the craniofacial defects caused by Fbrsl1 depletion. Based on these data, we propose that the disruption of the validated N-terminal isoforms of FBRSL1 at critical timepoints during embryogenesis leads to a hitherto undescribed complex neurodevelopmental syndrome.
Introduction In two unrelated children with a nearly identical clinical phenotype we performed trio-exome sequencing to uncover the underlying cause of a hitherto undiagnosed congenital malformation syndrome. In both affected children, we detected a de novo truncating variant in FBRSL1. Single exome sequencing and “reverse phenotyping” revealed a third patient having a truncating FBRSL1 mutation. The function of FBRSL1 is largely unknown and so Roser Ufartes and Hanna Berger have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02175-x) contains supplementary material, which is available to authorized users. * Annette Borchers borchers@uni‑marburg.de * Silke Pauli [email protected] Extended author information available on the last page of the article
far this gene has not been associated with any syndromic phenotype. Interestingly, mutations in the FBRSL1 paralogue AUTS2 (NG_034133.1, activator of transcription and developmental regulator) were first described in 2013 as causative of an intellectual disability syndrome with microcephaly and, in some cases, additional features like heart defects and co
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