Candidate Genes Associated with Delayed Neuropsychomotor Development and Seizures in a Patient with Ring Chromosome 20

Abstract

Ring chromosome 20 (r20) is characterized by intellectual impairment, behavioral disorders, and refractory epilepsy. We report a patient presenting nonmosaic ring chromosome 20 followed by duplication and deletion in 20q13.33 with seizures, delayed neuropsychomotor development and language, mild hypotonia, low weight gain, and cognitive deficit. Chromosomal microarray analysis (CMA) enabled us to restrict a chromosomal segment and thus integrate clinical and molecular data with systems biology. With this approach, we were able to identify candidate genes that may help to explain the consequences of deletions in 20q13.33. In our analysis, we observed five hubs (ARFGAP1, HELZ2, COL9A3, PTK6, and EEF1A2), seven bottlenecks (CHRNA4, ARFRP1, GID8, COL9A3, PTK6, ZBTB46, and SRMS), and two H-B nodes (PTK6 and COL9A3). The candidate genes may play an important role in the developmental delay and seizures observed in r20 patients. Gene ontology included microtubule-based movement, nucleosome assembly, DNA repair, and cholinergic synaptic transmission. Defects in these bioprocesses are associated with the development of neurological diseases, intellectual disability, neuropathies, and seizures. Therefore, in this study, we can explore molecular cytogenetic data, identify proteins through network analysis of protein-protein interactions, and identify new candidate genes associated with the main clinical findings in patients with 20q13.33 deletions.

Figure 1

(A) Chromosome banding showing the chromosome 20 pair, with a normal chromosome and the other on the ring (20). (B) CMA profile of chromosome 20 showing the hybridization pattern. The genomic segment with a gain of ∼302,774 kb (61,142,577–61,445,350) is shown (vertical blue band). The arrow indicates the shift of the median ratio log² to +1.0. The segment with loss of ∼1.4 Mb (61,472,348–62,872,839) is demonstrated (vertical red band). The arrow indicates the shift of the median ratio log² to −1.0.

Figure 2

PPI network. A list of 40 genes and gene predictions was obtained from the human assembly of February 2009 (GRCh37/hg19) (). Interaction data from STRING were used to construct networks using cytoscape software. (A) The primary network is composed of 1,572 nodes (proteins) and 54,925 edges (interactions). (B) The secondary network is composed of 794 nodes and 16,805 edges; yellow nodes are candidate proteins with data available in string (ZGPAT, HELZ2, EEF1A2, TNFRSF6B, ZBTB46, DIDO1, ARFGAP1, RTEL1, SRMS, GMEB2, YTHDF1, PTK6, GID8, BIRC7, COL9A3, COL20A1, KCNQ2, ARFRP1, and CHRNA4). (C) Cluster 2, with C_i = 40,863, is composed of 510 nodes and 10,388 edges. Nodes with green borders are considered hubs; orange are bottlenecks; and red are hub bottlenecks.

Figure 3

Summary of the bioprocess enrichment identified in cluster 2. The colored horizontal bars show GO terms frequently present.