Abstract
Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a ‘genotype first’ approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.
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Acknowledgements
We would like to thank Drs J Andrieux, N Van der Aa, L Bird, T Cole, K Neas, F Faletra, T de Ravel, N Morrison, four useful and additional information required for several patients in free Databases. This work was supported by a grant from REDES/FIBHULP08 of the Fundación para la Investigación Biomédica Hospital Universitario la Paz, the ENDOSCREEN project from Comunidad Autonóma de Madrid, FIS 011/2491 from ISCIII and the EUCID-COST Action BM-1208.
Author Contributions
MAM, MPB, EV and JN performed the microarray analysis. JAT did the punctual mutational analysis of PIAS4 gene. MLT, AD and BF did the cytogenetic and FISH studies. IRA and MVFM did Sanger sequencing analysis. IRA and RM did the detection of breakpoints and the junction fragment analysis. RMA and MCC performed the aCGH studies. JN, FSS, SGM, PDL, AD, MC, AP, LD, MO, MCSH, ECF, ASJ, GG, LA, CHE, SS, ED, XL, HD, DBB, SV, MBD, JWE, SR, CAVV, FFR did the clinical characterization of the patients described herein. JAR, KWG, PL and JN wrote the paper in consultation with all the other authors.
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Nevado, J., Rosenfeld, J., Mena, R. et al. PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome. Eur J Hum Genet 23, 1615–1626 (2015). https://doi.org/10.1038/ejhg.2015.51
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DOI: https://doi.org/10.1038/ejhg.2015.51
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