, Volume 20, Issue 3, pp 145–154 | Cite as

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

  • Maria Teresa BonatiEmail author
  • Chiara Castronovo
  • Alessandra Sironi
  • Dario Zimbalatti
  • Ilaria Bestetti
  • Milena Crippa
  • Antonio Novelli
  • Sara Loddo
  • Maria Lisa Dentici
  • Juliet Taylor
  • Françoise Devillard
  • Lidia Larizza
  • Palma Finelli
Original Article


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.


9q34 duplication syndrome Kleefstra syndrome EHMT1 9q34.3 microduplications Neurodevelopmental disorders Autism 



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 and via email from Funding for the project was provided by the Wellcome Trust.


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

Compliance with ethical standards

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.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Supplementary material

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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)

10048_2019_581_MOESM1_ESM.tif (5 mb)
High Resolution Image (TIF 5110 kb)
10048_2019_581_Fig4_ESM.png (14 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)

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High Resolution Image (TIF 470 kb)
10048_2019_581_MOESM3_ESM.docx (19 kb)
Supplementary Table 1 (DOCX 18 kb)
10048_2019_581_MOESM4_ESM.docx (25 kb)
Supplementary Table 2a (DOCX 25 kb)
10048_2019_581_MOESM5_ESM.docx (21 kb)
Supplementary Table 2b (DOCX 20 kb)
10048_2019_581_MOESM6_ESM.xlsx (23 kb)
Supplementary Table 3 (XLSX 23 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Maria Teresa Bonati
    • 1
    Email author
  • Chiara Castronovo
    • 2
  • Alessandra Sironi
    • 2
    • 3
  • Dario Zimbalatti
    • 1
  • Ilaria Bestetti
    • 2
    • 3
  • Milena Crippa
    • 2
    • 3
  • Antonio Novelli
    • 4
  • Sara Loddo
    • 4
  • Maria Lisa Dentici
    • 5
  • Juliet Taylor
    • 6
  • Françoise Devillard
    • 7
  • Lidia Larizza
    • 2
  • Palma Finelli
    • 2
    • 3
  1. 1.Istituto Auxologico Italiano, IRCCSClinic of Medical GeneticsMilanItaly
  2. 2.Research Lab of Medical Cytogenetics and Molecular GeneticsIstituto Auxologico Italiano, IRCCSMilanItaly
  3. 3.Department of Medical Biotechnology and Translational MedicineUniversità degli Studi di MilanoMilanItaly
  4. 4.Laboratory of Medical GeneticsBambino Gesù Children’s Hospital, IRCCSRomeItaly
  5. 5.Medical Genetics UnitBambino Gesù Children’s Hospital, IRCCSRomeItaly
  6. 6.Genetic Health Service New Zealand – Northern HubAucklandNew Zealand
  7. 7.Département de Génétique et Procréation Hôpital Couple-EnfantCHU Grenoble AlpesGrenobleFrance

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