Authors: Luigia Cinque, Lucia Micale, Elena Manara, Andrea Esposito, Orazio Palumbo, Andrea Maria Chiariello, Simona Bianco, Giulia Guerri, Matteo Bertelli, Maria Grazia Giuffrida, Laura Bernardini, Angelantonio Notarangelo, Mario Nicodemi & Marco Castori


  • Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013, San Giovanni Rotondo, Foggia, Italy
  • MAGI Euregio, San Felice del Benaco, Brescia, Italy
  • Dipartimento di Fisica, Università degli Studi di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, Naples, Italy
  • Berlin Institute for Medical Systems Biology, Max-Delbrück Centre (MDC) for Molecular Medicine, Berlin, Germany
  • EBTNA-LAB, San Felice del Benaco, Brescia, Italy

Publication: Human Genetics

Date: November 2021

Full paper:


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.