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

Abstract

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.

International meeting on Wolf‐Hirschhorn syndrome: Update on the nosology and new insights on the pathogenic mechanisms for seizures and growth delay

“…(i) Highlighting a major role of WHSC1 (NSD2) gene in the pathogenesis of the WHS main features (ID, characteristic facies, growth and developmental delay), in fact all these works suggest; that truncating variants on NSD2 gene will lead to atypical clinical manifestations of WHS, not including the epilepsy (Barrie et al, 2019;Boczek et al, 2018;Cammarata-Scalisi et al, 2019;Corrêa et al, 2018;Hirschhorn, 2008;Jiang et al, 2019):…”

Network‐based analysis using chromosomal microdeletion syndromes as a model

“…The investigation of protein-coding genes located in the critical regions of chromosomes using a platform of PPI indicated that MSNproteins were likely to be located in specific regions of the interactome (Corrêa et al, 2018;Corrêa, Feltes, Poswar, & Riegel, 2020;Corrêa, Feltes, & Riegel, 2019;Corrêa, Venâncio, Galera, & Riegel, 2020). Disease-associated proteins usually interact with each other in a local neighborhood of the human interactome more frequently than expected by chance (Goh et al, 2007;Oti et al, 2006;Vidal et al, 2011).…”

Contribution of Congenital Heart Disorders Associated With Copy Number Variants in Mediating Risk for Brain Developmental Disorders: Evidence From 20-Year Retrospective Cohort Study

“…The results of this search suggest that the genes affected by copy number variation at each of these four loci play important roles in a variety of biological processes that associated with physiology both in the brain and the heart (Figure 5A). It follows, therefore, that the deletion/duplication of genetic locus involved in these functions may critically disrupt pathways involved in both heart and brain development (Figure 5B), potentially by a complex molecular mechanism (23)(24)(25)(26). Additionally, disruption to heart development may have secondary consequences for brain development.…”