Abstract
Patau Syndrome (PS), characterized as a lethal disease, allows less than 15% survival over the first year of life. Most deaths owe to brain and heart disorders, more so due to septal defects because of altered gene regulations. We ascertained the cytogenetic basis of PS first, followed by molecular analysis and docking studies. Thirty-seven PS cases were referred from the Department of Pediatrics, King Abdulaziz University Hospital to the Center of Excellence in Genomic Medicine Research, Jeddah during 2008 to 2018. Cytogenetic analyses were performed by standard G-band method and trisomy13 were found in all the PS cases. Studies have suggested that genes of chromosome 13 and other chromosomes are associated with PS. We, therefore, did molecular pathway analysis, gene interaction, and ontology studies to identify their associations. Genomic analysis revealed important chr13 genes such as FOXO1, Col4A1, HMGBB1, FLT1, EFNB2, EDNRB, GAS6, TNFSF1, STARD13, TRPC4, TUBA3C, and TUBA3D, and their regulatory partners on other chromosomes associated with cardiovascular disorders, atrial and ventricular septal defects. There is strong indication of involving FOXO1 (Forkhead Box O1) gene—a strong transcription factor present on chr13, interacting with many septal defects link genes. The study was extended using molecular docking to find a potential drug lead for overexpressed FOXO1 inhibition. The phenothiazine and trifluoperazine showed efficiency to inhibit overexpressed FOXO1 protein, and could be potential drugs for PS/trisomy13 after validation.
Highlights
Patau Syndrome (PS) is a rare congenital anomaly due to the presence of an extra chromosome 13 popularly called trisomy 13 [1]
Molecular interactions study of 308 protein coding genes located on chromosome 13 led to identification of significant genes such as: Forkhead Box O1 (FOXO1), RB1, CCNA1, TFDP1, KL, IRS2, F10, F7 GJB6, GJA3, TUBA3C/TUBA3D, COL4A1, FLT1, KLF12, and Zic family member 2 (ZIC2)
Molecular network analysis and protein–protein interaction study indicated FOXO1 as strong transcription factor which interacts with other key genes like GATA4, CITED and TBX5 located on different chromosomes but associated with lethal heart disorders in PS
Summary
Patau Syndrome (PS) is a rare congenital anomaly due to the presence of an extra chromosome 13 popularly called trisomy 13 [1]. In spite of being the least common, it is the severest of all autosomal trisomies indicated by a prevalence rate of 1:5000 to 1:20,000 [2,3]. The syndrome is associated with a host of congenital anomalies including central nervous system (CNS) defects, midline abnormalities, eye and ear anomalies, cardiac defects, apnea, orofacial flaws, gastrointestinal and genitourinary aberrations, limb deformations, and developmental retardation [4,5]. Death of PS is assigned to frequent CNS and cardiopulmonary system aberrations [12]
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