Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. N. Gosset1, P. Chetaille2, J.-M. Côté2, C. Houde2, C. Preuss1, S. Burkharda3, J. Castilloux2, J. Piché1, S. Leclerc1, F. Wünnemann1, M. Thilbault1, C. Gagnon1, A. Galli4, E. Tuck4, G.-R. X. Hickson5, N. El Amine5, F. LeDeist5, E. Lemyre5, P. De Santa Barbara6, S. Faure6, A. Jonzon7, M. Cameron1, H. Dietz8, E. Gallo-McFarlane8, W. Benson9, Y. Shen10, M. Jomphe11, S.-J. M. Jones10, J. Bakkers3, G. Andelfinger1 1) Cardiovascular Genetics, CHU Sainte Justine Research Center, Montreal, Quebec, Canada; 2) Centre Mère Enfants Soleil, CHU de Québec, Québec, QC, Canada; 3) Hubrecht Institute, Utrecht, The Netherlands; 4) The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; 5) Department of Pediatrics, University of Montréal, Montréal, Québec, Canada; 6) INSERM U1046, Montpellier Cedex, France; 7) Astrid Lindgrens Childrens Hospital, Uppsala University, Uppsala, Sweden; 8) Johns Hopkins University School of Medicine, Howard Hughes Medical Institute, Baltimore, MD, USA; 9) Childrens Hospital of Wisconsin, Milwaukee, WI, USA; 10) Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; 11) Projet BALSAC, Université du Québec à Chicoutimi, QC, Canada.

   Disturbances of pacemaker activity in the heart and the gut can have varied clinical manifestations. In the heart, dysregulation of the sinus node results in sick sinus syndrome (SSS), the most common cause of pacemaker implantation. In the gut, pacemaking is mediated through the network of interstitial cells of Cajal and the autonomous enteric nervous system. Chronic intestinal pseudo-obstruction (CIPO) is a rare and severe disorder of gastrointestinal motility, in which intestinal obstruction occurs in the absence of a mechanical obstacle. Here, we describe a new syndrome characterized by Chronic atrial and intestinal dysrhythmia, termed CAID syndrome. We identified a cohort of 17 subjects in whom SSS and CIPO co-occurred during the first four decades of life including 16 French Canadian and one Swedish patient. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Whole-exome sequencing and genetic fine mapping of the disease associated haplotype revealed a northern European origin for the rare haplotype on which the ultra-rare mutation (1/8598 in NHLBI exome dataset) recently arose. Genealogical analysis traced back the most common ancestors to a founder couple married in 1620 in France supporting the idea of a transatlantic founder effect. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycling, increased senescence and enhanced activation of TGF- signaling. Karyotypes show the typical railroad appearance of a centromeric cohesion defect. Patient tissues display pathological changes of both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated abnormalities seen in humans with CAID syndrome. Taken together, our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm.

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