Abstract
Intellectual disability (ID) comprises a large group of heterogeneous disorders, often without a known molecular cause. X-linked ID accounts for 5–10% of male ID cases. We investigated a large, three-generation family with mild ID and behavior problems in five males and one female, with a segregation suggestive for X-linked inheritance. Linkage analysis mapped a disease locus to a 7.6 Mb candidate region on the X-chromosome (LOD score 3.3). Whole-genome sequencing identified a 2 bp insertion in exon 2 of the chromosome X open reading frame 56 gene (CXorf56), resulting in a premature stop codon. This insertion was present in all intellectually impaired individuals and carrier females. Additionally, X-inactivation status showed skewed methylation patterns favoring the inactivation of the mutated allele in the unaffected carrier females. We demonstrate that the insertion leads to nonsense-mediated decay and that CXorf56 mRNA expression is reduced in the impaired males and female. In murine brain slices and primary hippocampal neuronal cultures, CXorf56 protein was present and localized in the nucleus, cell soma, dendrites, and dendritic spines. Although no other families have been identified with pathogenic variants in CXorf56, these results suggest that CXorf56 is the causative gene in this family, and thus a novel candidate gene for X-linked ID with behavior problems.
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Acknowledgements
We thank the family for their continuous cooperation, their endless patience, perseverance, and trust. We thank Diana van Rongen-Nispen and Lorette Dubbel-Hulsman for cell culture, Dicky Halley and Hans van Bokhoven for availability of DNA samples, and Edith Friesema and Theo Visser for supporting the project. Tom de Vries Lentsch is acknowledged for excellent graphical support. We thank Willem Verhoeven and collaborators of the Vincent van Gogh institute for performing IQ tests of family members.
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Verkerk, A.J.M.H., Zeidler, S., Breedveld, G. et al. CXorf56, a dendritic neuronal protein, identified as a new candidate gene for X-linked intellectual disability. Eur J Hum Genet 26, 552–560 (2018). https://doi.org/10.1038/s41431-017-0051-9
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DOI: https://doi.org/10.1038/s41431-017-0051-9
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