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9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression

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Abstract

Both copy number losses and gains occur within subtelomeric 9q34 region without common breakpoints. The microdeletions cause Kleefstra syndrome (KS), whose responsible gene is EHMT1. A 9q34 duplication syndrome (9q34 DS) had been reported in literature, but it has never been characterized by a detailed molecular analysis of the gene content and endpoints. To the best of our knowledge, we report on the first patient carrying the smallest 9q34.3 duplication containing EHMT1 as the only relevant gene. We compared him with 21 reported patients described here as carrying 9q34.3 duplications encompassing the entire gene and extending within ~ 3 Mb. By surveying the available clinical and molecular cytogenetic data, we were able to discover that similar neurodevelopmental disorders (NDDs) were shared by patient carriers of even very differently sized duplications. Moreover, some facial features of the 9q34 DS were more represented than those of KS. However, an accurate in silico analysis of the genes mapped in all the duplications allowed us to support EHMT1 as being sufficient to cause a NDD phenotype. Wider patient cohorts are needed to ascertain whether the rearrangements have full causative role or simply confer the susceptibility to NDDs and possibly to identify the cognitive and behavioral profile associated with the increased dosage of EHMT1.

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Acknowledgments

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 the project was provided by the Wellcome Trust.

Funding

This study was funded by Ministry of Health “Ricerca Corrente” (grant numbers 08C607_2006, 08C602_2006, and 08C204_2012) to IRCCS Istituto Auxologico Italiano.

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Author notes

  1. Maria Teresa Bonati and Chiara Castronovo made equal contributions and should therefore both be considered as first author

Authors and Affiliations

  1. Istituto Auxologico Italiano, IRCCS, Clinic of Medical Genetics, Piazzale Brescia 20, 20149, Milan, Italy

    Maria Teresa Bonati & Dario Zimbalatti

  2. Research Lab of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, IRCCS, 20145, Milan, Italy

    Chiara Castronovo, Alessandra Sironi, Ilaria Bestetti, Milena Crippa, Lidia Larizza & Palma Finelli

  3. Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Segrate, 20090, Milan, Italy

    Alessandra Sironi, Ilaria Bestetti, Milena Crippa & Palma Finelli

  4. Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital, IRCCS, 00146, Rome, Italy

    Antonio Novelli & Sara Loddo

  5. Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146, Rome, Italy

    Maria Lisa Dentici

  6. Genetic Health Service New Zealand – Northern Hub, Auckland, New Zealand

    Juliet Taylor

  7. Département de Génétique et Procréation Hôpital Couple-Enfant, CHU Grenoble Alpes, 38043, Grenoble, France

    Françoise Devillard

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  1. Maria Teresa Bonati
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Correspondence to Maria Teresa Bonati.

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Informed consent was obtained from all individual participants included in the study or their legal guardians. Signed informed consent for publication of patient 1’s photographs was obtained from his mother. The study was approved by the Ethical Clinical Research Committee of IRCCS Istituto Auxologico Italiano.

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Supplementary Fig. 1

Array-CGH analysis identifies two rare inherited CNVs: a paternal 399 kb duplication at 1p36.11 (chr1:25320307–25,719,620, hg19) (upper panel), and a maternal 24 kb gain at Xq22.3 (chrX:104155507–104,179,536, hg19) (lower panel) (PNG 1163 kb)

High Resolution Image (TIF 5110 kb)

Supplementary Fig. 2

Scatter plots, obtained using TaqMan probes, show increased SYF2 expression in P1 (Pt) and his father (F) (circular dot) compared to 10 normal individuals (Ctrls, circular dots). The horizontal dotted bars in the control expression indicate the range between mean ± 2 standard deviation values (PNG 14 kb)

High Resolution Image (TIF 470 kb)

Supplementary Table 1

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Supplementary Table 2a

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Supplementary Table 2b

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Supplementary Table 3

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Bonati, M.T., Castronovo, C., Sironi, A. et al. 9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression. Neurogenetics 20, 145–154 (2019). https://doi.org/10.1007/s10048-019-00581-6

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