Balanced chromosomal rearrangements offer insights into coding and noncoding genomic features associated with developmental disorders
Authors: Lowther Chelsea , Mehrjouy Mana M. , Collins Ryan L. , Bak Mads C. , Dudchenko Olga , Brand Harrison , Dong Zirui , Rasmussen Malene B. , Gu Huiya , Weisz David , Nazaryan-Petersen Lusine , Fjorder Amanda S. , Mang Yuan , Lind-Thomsen Allan , Mendez Juan M.M. , Calle Xabier , Chopra Anuja , Hansen Claus , Bugge Merete , Broekema Roeland V. , Varilo Teppo , Luukkonen Tiia , Engelen John , Vianna-Morgante Angela M. , Fonseca Ana Carolina S. , Mazzeu Juliana F. , Dornelles-Wawruk Halinna , Abe Kikue T. , Vermeesch Joris R. , Van Den Bogaert Kris , Sismani Carolina , Aristidou Constantia , Evangelidou Paola , Schinzel Albert A. , Sanlaville Damien , Schluth-Bolard Caroline , Kalscheuer Vera M. , Wenzel Maren , Kim Hyung-Goo , Õunap Katrin , Roht Laura , Midyan Susanna , Bonaglia Maria C. , Lindstrand Anna , Eisfeldt Jesper , Ottosson Jesper , Nilsson Daniel , Pettersson Maria , Bastos Elenice F. , Rajcan-Separovic Evica , Silan Fatma , Sheth Frenny J. , Novelli Antonio , Frengen Eirik , Fannemel Madeleine , Strømme Petter , Vokač Nadja Kokalj , Daumer-Haas Cornelia , Moretti-Ferreira Danilo , de Souza Deise Helena , Ramos-Arroyo Maria A. , Igoa Maria M. , Angelova Lyudmila , Kroisel Peter M. , Rey Graciela del , Vieira Társis A.P. , Lewis Suzanne , Hao Wang , Drabova Jana , Havlovicova Marketa , Hancarova Miroslava , Sedláček Zdeněk , Vogel Ida , Hjortshøj Tina D. , Møller Rikke S. , Tümer Zeynep , Fagerberg Christina , Ousager Lilian B. , Schönewolf-Greulich Bitten , Lauridsen Mathilde , Piard Juliette , Pebrel-Richard Celine , Jaillard Sylvie , Ehmke Nadja , Stefanou Eunice G. , Marta Czakó , György Kosztolányi , Dalal Ashwin , Dutta Usha R. , Shukla Rashmi , Lonardo Fortunato , Zuffardi Orsetta , Houge Gunnar , Misceo Doriana , Baig Shahid M. , Midro Alina , Wawrusiewicz-Kurylonek Natalia , Carreira Isabel M. , Melo Joana B. , Martinez Laura Rodriguez , Guitart Miriam , Lovmar Lovisa , Gullander Jacob , Hansson Kerstin B.M. , de Almeida Esteves Cynthia , Akkari Yassmine , Batanian Jacqueline R. , Li Xu , Lespinasse James , Silahtaroglu Asli , Harding Christina Halgren , Krogh Lotte Nylandsted , Taylor Juliet , Lehnert Klaus , Hill Rosamund , Snell Russell G. , Samson Christopher A. , Jacobsen Jessie C. , Levy Brynn , Clark Ozden Altiok , Toylu Asli , Nur Banu , Mihci Ercan , O’Keefe Kathryn , Mohajeri-Stickels Kiana , Wilch Ellen S. , Kammin Tammy , Piña-Aguilar Raul E. , Nalbandian Katarena , Temel Sehime G. , Sag Sebnem Ozemri , Turkgenc Burcu , Kamath Arveen , Ruiz-Herrera Adriana , Banka Siddharth , Schilit Samantha L.P. , Currall Benjamin B. , Yachelevich Naomi , Galloway Stephanie , Chung Wendy K. , Raskin Salmo , Maya Idit , Orenstein Naama , Gilad Nesia Kropach , Flamenbaum Kayla R. , Hay Beverly N. , Morton Cynthia C. , Liao Eric , Choy Kwong Wai , Gusella James F. , Jacky Peter , Aiden Erez Lieberman ,   International Breakpoint Mapping Consortium (IBMC),   Danish Cytogenetic Central Registry Study Group,   Developmental Genome Anatomy Project (DGAP), Bache Iben , Talkowski Michael E. , Tommerup Niels 
Published: February 2022

Balanced chromosomal rearrangements (BCRs), including inversions, translocations, and insertions, reorganize large sections of the genome and contribute substantial risk for developmental disorders (DDs). However, the rarity and lack of systematic screening for BCRs in the population has precluded unbiased analyses of the genomic features and mechanisms associated with risk for DDs versus normal developmental outcomes. Here, we sequenced and analyzed 1,420 BCR breakpoints across 710 individuals, including 406 DD cases and the first large-scale collection of 304 control BCR carriers. We found that BCRs were not more likely to disrupt genes in DD cases than controls, but were seven-fold more likely to disrupt genes associated with dominant DDs (21.3% of cases vs. 3.4% of controls; P = 1.60×10−12). Moreover, BCRs that did not disrupt a known DD gene were significantly enriched for breakpoints that altered topologically associated domains (TADs) containing dominant DD genes in cases compared to controls (odds ratio [OR] = 1.43, P = 0.036). We discovered six TADs enriched for noncoding BCRs (false discovery rate < 0.1) that contained known DD genes (MEF2C, FOXG1, SOX9, BCL11A, BCL11B, and SATB2) and represent candidate pathogenic long-range positional effect (LRPE) loci. These six TADs were collectively disrupted in 7.4% of the DD cohort. Phased Hi-C analyses of five cases with noncoding BCR breakpoints localized to one of these putative LRPEs, the 5q14.3 TAD encompassing MEF2C, confirmed extensive disruption to local 3D chromatin structures and reduced frequency of contact between the MEF2C promoter and annotated enhancers. We further identified six genomic features enriched in TADs preferentially disrupted by noncoding BCRs in DD cases versus controls and used these features to build a model to predict TADs at risk for LRPEs across the genome. These results emphasize the potential impact of noncoding structural variants to cause LRPEs in unsolved DD cases, as well as the complex interaction of features associated with predicting three-dimensional chromatin structures intolerant to disruption.