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A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome

Item Type:Article
Title:A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome
Creators Name:Cinque, L. and Micale, L. and Manara, E. and Esposito, A. and Palumbo, O. and Chiariello, A.M. and Bianco, S. and Guerri, G. and Bertelli, M. and Giuffrida, M.G. and Bernardini, L. and Notarangelo, A. and Nicodemi, M. and Castori, M.
Abstract:Cooks syndrome (CS) is an ultrarare limb malformation due to in tandem microduplications involving KCNJ2 and extending to the 5' regulatory element of SOX9. To date, six CS families were resolved at the molecular level. Subsequent studies explored the evolutionary and pathological complexities of the SOX9-KCNJ2/Sox9-Kcnj2 locus, and suggested a key role for the formation of novel topologically associating domain (TAD) by inter-TAD duplications in causing CS. Here, we report a unique case of CS associated with a de novo 1;17 translocation affecting the KCNJ2 locus. On chromosome 17, the breakpoint mapped between KCNJ16 and KCNJ2, and combined with a ~ 5 kb deletion in the 5' of KCNJ2. Based on available capture Hi-C data, the breakpoint on chromosome 17 separated KCNJ2 from a putative enhancer. Gene expression analysis demonstrated downregulation of KCNJ2 in both patient's blood cells and cultured skin fibroblasts. Our findings suggest that a complex rearrangement falling in the 5' of KCNJ2 may mimic the developmental consequences of in tandem duplications affecting the SOX9-KCNJ2/Sox9-Kcnj2 locus. This finding adds weight to the notion of an intricate role of gene regulatory regions and, presumably, the related three-dimensional chromatin structure in normal and abnormal human morphology.
Keywords:Chromosome Breakpoints, Pair 1 Human Chromosomes, Pair 17 Human Chromosomes, Facies, Fingers, Congenital Foot Deformities, Gene Rearrangement, Congenital Hand Deformities, Fluorescence in Situ Hybridization, Inwardly Rectifying Potassium Channels, Nucleic Acid Regulatory Sequences, Sequence Deletion, Genetic Translocation, Young Adult
Source:Human Genetics
Page Range:217-227
Date:February 2022
Official Publication:https://doi.org/10.1007/s00439-021-02403-y
PubMed:View item in PubMed

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