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Front. Genet. | doi: 10.3389/fgene.2019.01074

Molecular and clinical characterization of a novel nonsense variant in exon 1 of the UPF3B gene found in a large Spanish Basque family (MRX82)

 María I. Tejada1, 2, 3*,  Olatz Villate1, 2, 3,  Nekane Ibarluzea1, 2,  Ana-Belén De la Hoz1, 2, Cristina Martínez-Bouzas1, 2, 3, Elena Beristain4, Francisco Martínez5, Michael J. Friez6, Beatriz Sobrino7 and Francisco Barros7
  • 1Center for Biomedical Research in the Network of Rare Diseases (CIBERER), Spain
  • 2Biocruces Bizkaia Health Research Institute, Spain
  • 3Cruces University Hospital, Spain
  • 4Araba University Hospital, Spain
  • 5University and Polytechnic Hospital of La Fe, Spain
  • 6Greenwood Genetic Center, United States
  • 7Galician Public Foundation of Genomic Medicine, Spain

X-linked intellectual disability (XLID) is known to explain up to 10% of the intellectual disability in males. A large number of families in which intellectual disability is the only clinically consistent manifestation have been described. While linkage analysis and candidate gene testing were the initial approaches to find genes and variants, next generation sequencing (NGS) has accelerated the discovery of more and more XLID genes. Using NGS, we resolved the genetic cause of MRX82 (OMIM number 300518), a large Spanish Basque family with five affected males with intellectual disability and a wide phenotypic variability among them despite having the same pathogenic variant. Although the previous linkage study had mapped the locus to aninterval of 7.6Mb in Xq24-Xq25 of the X chromosome, this region contained too many candidate genes to be analysed using conventional approaches. NGS revealed a novel nonsense variant: c.118C>T; p.Gln40* in UPF3B, a gene previously implicated in XLID that encodes a protein involved in nonsense-mediated mRNA decay (NMD). Further molecular studies showed that the mRNA transcript was not completely degraded by NMD. However, UPF3B protein was not detected by conventional Western Blo tanalysis at least downstream of the 40 residue demonstrating that the phenotype could be due to the loss of functional protein. This is the first report of a premature termination codon before the three functional domains of the UPF3B protein and these results directly implicate the absence of these domains with XLID, autism and some dysmorphic features.

Keywords: UPF3B gene, Next Generation Sequencing - NGS, Intellectual disability (ID), Autism Spectrum Disoder, Non-Syndromic X linked Intellectual Disability

Received: 24 Jul 2019; Accepted: 08 Oct 2019.

Copyright: © 2019 Tejada, Villate, Ibarluzea, De la Hoz, Martínez-Bouzas, Beristain, Martínez, Friez, Sobrino and Barros. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. María I. Tejada, Center for Biomedical Research in the Network of Rare Diseases (CIBERER), Valencia, 46010, Spain,