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BioMed Research International
Volume 2018, Article ID 5436187, 10 pages
Research Article

Cytogenomic Integrative Network Analysis of the Critical Region Associated with Wolf-Hirschhorn Syndrome

1Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), 91501-970 Porto Alegre, RS, Brazil
2Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-903 Porto Alegre, RS, Brazil
3Department of Pediatrics, Universidade Federal do Mato Grosso (UFMT), 78600-000 Cuiabá, MT, Brazil
4Post-Graduate Program in Genetics and Biodiversity, Universidade Federal da Bahia, Campus Ondina, 40170-290 Salvador, BA, Brazil
5Institute of Biological Sciences, Universidade de Passo Fundo, Passo Fundo, RS, Brazil

Correspondence should be addressed to Mariluce Riegel; rb.ude.apch@legeirm

Received 6 October 2017; Accepted 1 February 2018; Published 12 March 2018

Academic Editor: Hesham H. Ali

Copyright © 2018 Thiago Corrêa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Deletions in the 4p16.3 region are associated with Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion syndrome involving variable size deletions. In this study, we perform a cytogenomic integrative analysis combining classical cytogenetic methods, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and systems biology strategies, to establish the cytogenomic profile involving the 4p16.3 critical region and suggest WHS-related intracellular cell signaling cascades. The cytogenetic and clinical patient profiles were evaluated. We characterized 12 terminal deletions, one interstitial deletion, two ring chromosomes, and one classical translocation 4;8. CMA allowed delineation of the deletions, which ranged from 3.7 to 25.6 Mb with breakpoints from 4p16.3 to 4p15.33. Furthermore, the smallest region of overlapping (SRO) encompassed seven genes in a terminal region of 330 kb in the 4p16.3 region, suggesting a region of susceptibility to convulsions and microcephaly. Therefore, molecular interaction networks and topological analysis were performed to understand these WHS-related symptoms. Our results suggest that specific cell signaling pathways including dopamine receptor, NAD+ nucleosidase activity, and fibroblast growth factor-activated receptor activity are associated with the diverse pathological WHS phenotypes and their symptoms. Additionally, we identified 29 hub-bottlenecks (H-B) nodes with a major role in WHS.