Abstract
Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIX gene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIX are responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-type concept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.
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Acknowledgements
We thank the patients and their families for participating in this study. We thank Wallid Deb from Universitary Hospital of Nantes for additional data supply, Dr Lucile Pinson and Dr Anouck Schneider from Universitary Hospital of Montpelier and Hilde van Esch from KU Leuven for the constructive discussions about their patients. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for this project was provided by the Wellcome Trust. We thank Arthur Sorlin, Dr Julia Lauer Zillhardt and Pr Damien Sanlaville for their help during the use of this database.
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Trimouille, A., Houcinat, N., Vuillaume, ML. et al. 19p13 microduplications encompassing NFIX are responsible for intellectual disability, short stature and small head circumference. Eur J Hum Genet 26, 85–93 (2018). https://doi.org/10.1038/s41431-017-0037-7
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DOI: https://doi.org/10.1038/s41431-017-0037-7
