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1. Comparative 3D genome analysis between neural retina and retinal pigment epithelium reveals differential cis-regulatory interactions at retinal disease loci

Author

D’haene, Eva, López-Soriano, Víctor, Martínez-García, Pedro Manuel, Kalayanamontri, Soraya, Rey, Alfredo Dueñas, Sousa-Ortega, Ana, Naranjo, Silvia, Van de Sompele, Stijn, Vantomme, Lies, Mahieu, Quinten, Vergult, Sarah, Neto, Ana, Gómez-Skarmeta, José Luis, Martínez-Morales, Juan Ramón, Bauwens, Miriam, Tena, Juan Jesús, and De Baere, Elfride

Published
2024
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2. A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development

Author

Wilderman, Andrea, D’haene, Eva, Baetens, Machteld, Yankee, Tara N., Winchester, Emma Wentworth, Glidden, Nicole, Roets, Ellen, Van Dorpe, Jo, Janssens, Sandra, Miller, Danny E., Galey, Miranda, Brown, Kari M., Stottmann, Rolf W., Vergult, Sarah, Weaver, K. Nicole, Brugmann, Samantha A., Cox, Timothy C., and Cotney, Justin

Published
2024
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3. Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability

Author

Agrawal, Pankaj, Armstrong Scott, Daryl, Barkoudah, Elizabeth, Bellini, Melissa, Beneteau, Claire, Bjørgo, Kathrine, Brooks, Alice, Brown, Natasha, Castle, Alison, Castro, Diana, Chorin, Odelia, Cleghorn, Mark, Clement, Emma, Coman, David, Costin, Carrie, Devriendt, Koen, Dong, Dexin, Dries, Annika, Duelund Hjortshøj, Tina, Dyment, David, Eng, Christine, Genetti, Casie, Grano, Siera, Henneman, Peter, Heron, Delphine, Hoffmann, Katrin, Hom, Jason, Du, Haowei, Iascone, Maria, Isidor, Bertrand, Järvelä, Irma E., Jones, Julie, Keren, Boris, Koenig, Mary Kay, Kohlhase, Jürgen, Lalani, Seema, Le Caignec, Cedric, Lewis, Andi, Liu, Pengfei, Lovgren, Alysia, Lupski, James R., Lyons, Mike, Lysy, Philippe, Manning, Melanie, Marcelis, Carlo, McLean, Scott Douglas, Mercie, Sandra, Mertens, Mareike, Molin, Arnaud, Nizon, Mathilde, Nugent, Kimberly Margaret, Öhman, Susanna, O'Leary, Melanie, Okashah Littlejohn, Rebecca, Petit, Florence, Pfundt, Rolph, Pottocki, Lorraine, Raas-Rotschild, Annick, Ranguin, Kara, Revencu, Nicole, Rosenfeld, Jill, Rhodes, Lindsay, Santos Simmaro, Fernando, Sals, Karen, Schieving, Jolanda, Schrauwen, Isabelle, Schuurs-Hoeijmakers, Janneke H.M., Seaby, Eleanor G., Sheffer, Ruth, Snijders Blok, Lot, Sørensen, Kristina P., Srivastava, Siddharth, Stark, Zornitza, Stoeva, Radka, Stutterd, Chloe, Tan, Natalie B., Mathiesen Torring, Pernille, Vanakker, Olivier, van der Laan, Liselot, Ververi, Athina, Villavicencio-Lorini, Pablo, Vincent, Marie, Wand, Dorothea, Wessels, Marja, White, Sue, Wojcik, Monica H., Wu, Nan, Zhao, Sen, Pérez Baca, María del Rocío, Jacobs, Eva Z., Vantomme, Lies, Leblanc, Pontus, Bogaert, Elke, Dheedene, Annelies, De Cock, Laurenz, Haghshenas, Sadegheh, Foroutan, Aidin, Levy, Michael A., Kerkhof, Jennifer, McConkey, Haley, Chen, Chun-An, Batzir, Nurit Assia, Wang, Xia, Palomares, María, Carels, Marieke, Dermaut, Bart, Sadikovic, Bekim, Menten, Björn, Yuan, Bo, Vergult, Sarah, and Callewaert, Bert

Published
2024
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4. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author

Coursimault, Juliette, Guerrot, Anne-Marie, Morrow, Michelle M., Schramm, Catherine, Zamora, Francisca Millan, Shanmugham, Anita, Liu, Shuxi, Zou, Fanggeng, Bilan, Frédéric, Le Guyader, Gwenaël, Bruel, Ange-Line, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Tran Mau-Them, Frédéric, Tessarech, Marine, Colin, Estelle, El Chehadeh, Salima, Gérard, Bénédicte, Schaefer, Elise, Cogne, Benjamin, Isidor, Bertrand, Nizon, Mathilde, Doummar, Diane, Valence, Stéphanie, Héron, Delphine, Keren, Boris, Mignot, Cyril, Coutton, Charles, Devillard, Françoise, Alaix, Anne-Sophie, Amiel, Jeanne, Colleaux, Laurence, Munnich, Arnold, Poirier, Karine, Rio, Marlène, Rondeau, Sophie, Barcia, Giulia, Callewaert, Bert, Dheedene, Annelies, Kumps, Candy, Vergult, Sarah, Menten, Björn, Chung, Wendy K., Hernan, Rebecca, Larson, Austin, Nori, Kelly, Stewart, Sarah, Wheless, James, Kresge, Christina, Pletcher, Beth A., Caumes, Roseline, Smol, Thomas, Sigaudy, Sabine, Coubes, Christine, Helm, Margaret, Smith, Rosemarie, Morrison, Jennifer, Wheeler, Patricia G., Kritzer, Amy, Jouret, Guillaume, Afenjar, Alexandra, Deleuze, Jean-François, Olaso, Robert, Boland, Anne, Poitou, Christine, Frebourg, Thierry, Houdayer, Claude, Saugier-Veber, Pascale, Nicolas, Gaël, and Lecoquierre, François

Published
2022
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6. Comparative 3D genome analysis between neural retina and retinal pigment epithelium reveals differential cis-regulatory interactions at retinal disease loci.

Author

D'haene, Eva, López-Soriano, Víctor, Martínez-García, Pedro Manuel, Kalayanamontri, Soraya, Rey, Alfredo Dueñas, Sousa-Ortega, Ana, Naranjo, Silvia, Van de Sompele, Stijn, Vantomme, Lies, Mahieu, Quinten, Vergult, Sarah, Neto, Ana, Gómez-Skarmeta, José Luis, Martínez-Morales, Juan Ramón, Bauwens, Miriam, Tena, Juan Jesús, and De Baere, Elfride

Published
2024
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7. De novo missense variants in RAC3 cause a novel neurodevelopmental syndrome

Author

Costain, Gregory, Callewaert, Bert, Gabriel, Heinz, Tan, Tiong Y., Walker, Susan, Christodoulou, John, Lazar, Tamas, Menten, Björn, Orkin, Julia, Sadedin, Simon, Snell, Meaghan, Vanlander, Arnaud, Vergult, Sarah, White, Susan M., Scherer, Stephen W., Hayeems, Robin Z., Blaser, Susan, Wodak, Shoshana J., Chitayat, David, Marshall, Christian R., and Meyn, M. Stephen

Published
2019
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8. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

Author

Basilicata, M. Felicia, Bruel, Ange-Line, Semplicio, Giuseppe, Valsecchi, Claudia Isabelle Keller, Aktaş, Tuğçe, Duffourd, Yannis, Rumpf, Tobias, Morton, Jenny, Bache, Iben, Szymanski, Witold G., Gilissen, Christian, Vanakker, Olivier, Õunap, Katrin, Mittler, Gerhard, van der Burgt, Ineke, El Chehadeh, Salima, Cho, Megan T., Pfundt, Rolph, Tan, Tiong Yang, Kirchhoff, Maria, Menten, Björn, Vergult, Sarah, Lindstrom, Kristin, Reis, André, Johnson, Diana S., Fryer, Alan, McKay, Victoria, DDD Study, Fisher, Richard B., Thauvin-Robinet, Christel, Francis, David, Roscioli, Tony, Pajusalu, Sander, Radtke, Kelly, Ganesh, Jaya, Brunner, Han G., Wilson, Meredith, Faivre, Laurence, Kalscheuer, Vera M., Thevenon, Julien, and Akhtar, Asifa

Published
2018
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9. Comparative 3D genome analysis between neural retina and RPE reveals differentialcis-regulatory interactions at retinal disease loci

Author

D’haene, Eva, primary, Soriano, Victor López, additional, Martínez-García, Pedro Manuel, additional, Kalayanamontri, Soraya, additional, Dueñas Rey, Alfredo, additional, Sousa-Ortega, Ana, additional, Naranjo, Silvia, additional, Van de Sompele, Stijn, additional, Vantomme, Lies, additional, Mahieu, Quinten, additional, Vergult, Sarah, additional, Neto, Ana Bastos, additional, Gómez-Skarmeta, José Luis, additional, Martínez-Morales, Juan R., additional, Bauwens, Miriam, additional, Tena, Juan J., additional, and De Baere, Elfride, additional

Published
2023
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10. A novel neurodevelopmental syndrome caused by loss-of-function of the Zinc Finger Homeobox 3 (ZFHX3) gene

Author

del Rocío Pérez Baca, María, Jacobs, Eva Z., Vantomme, Lies, Leblanc, Pontus, Bogaert, Elke, Dheedene, Annelies, De Cock, Laurenz, Haghshenas, Sadegheh, Foroutan, Aidin, Levy, Michael A., Kerkhof, Jennifer, McConkey, Haley, Chen, Chun-An, Batzir, Nurit Assia, Wang, Xia, Palomares, Maria, Carels, Marieke, Demaut, Bart, Sadikovic, Bekim, Menten, Björn, Yuan, Bo, Vergult, Sarah, and Callewaert, Bert

Subjects
Article
Abstract

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function variation in ZFHX3 as a novel cause for syndromic intellectual disability (ID). ZFHX3, previously known as ATBF1, is a zinc-finger homeodomain transcription factor involved in multiple biological processes including cell differentiation and tumorigenesis. Through international collaboration, we collected clinical and morphometric data (Face2Gene) of 41 individuals with protein truncating variants (PTVs) or (partial) deletions of ZFHX3 . We used data mining, RNA and protein analysis to identify the subcellular localization and spatiotemporal expression of ZFHX3 in multiple in vitro models. We identified the DNA targets of ZFHX3 using ChIP seq. Immunoprecipitation followed by mass spectrometry indicated potential binding partners of endogenous ZFHX3 in neural stem cells that were subsequently confirmed by reversed co-immunoprecipitation and western blot. We evaluated a DNA methylation profile associated with ZFHX3 haploinsufficiency using DNA methylation analysis on whole blood extracted DNA of six individuals with ZFHX3 PTVs and four with a (partial) deletion of ZFHX3 . A reversed genetic approach characterized the ZFHX3 orthologue in Drosophila melanogaster . Loss-of-function variation of ZFHX3 consistently associates with (mild) ID and/or behavioural problems, postnatal growth retardation, feeding difficulties, and recognizable facial characteristics, including the rare occurrence of cleft palate. Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation in neural stem cells and SH-SY5Y cells, ZFHX3 interacts with the chromatin remodelling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex. In line with a role for chromatin remodelling, ZFHX3 haploinsufficiency associates with a specific DNA methylation profile in leukocyte-derived DNA. The target genes of ZFHX3 are implicated in neuron and axon development. In Drosophila melanogaster , z fh2, considered to be the ZFHX3 orthologue, is expressed in the third instar larval brain. Ubiquitous and neuron-specific knockdown of zfh2 results in adult lethality underscoring a key role for zfh2 in development and neurodevelopment. Interestingly, ectopic expression of zfh2 as well as ZFHX3 in the developing wing disc results in a thoracic cleft phenotype. Collectively, our data shows that loss-of-function variants in ZFHX3 are a cause of syndromic ID, that associates with a specific DNA methylation profile. Furthermore, we show that ZFHX3 participates in chromatin remodelling and mRNA processing.

Published
2023

11. Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

Author

Van de Sompele, Stijn, Small, Kent W., Cicekdal, Munevver Burcu, Soriano, Víctor López, D’haene, Eva, Shaya, Fadi S., Agemy, Steven, Van der Snickt, Thijs, Rey, Alfredo Dueñas, Rosseel, Toon, Van Heetvelde, Mattias, Vergult, Sarah, Balikova, Irina, Bergen, Arthur A., Boon, Camiel J.F., De Zaeytijd, Julie, Inglehearn, Chris F., Kousal, Bohdan, Leroy, Bart P., Rivolta, Carlo, Vaclavik, Veronika, van den Ende, Jenneke, van Schooneveld, Mary J., Gómez-Skarmeta, José Luis, Tena, Juan J., Martinez-Morales, Juan R., Liskova, Petra, Vleminckx, Kris, De Baere, Elfride, Human Genetics, ANS - Complex Trait Genetics, ARD - Amsterdam Reproduction and Development, Ophthalmology, Ghent University, European Commission, Foundation Fighting Blindness, and Research Foundation - Flanders

Subjects
Adult, EXPRESSION, DOMAINS, PHOTORECEPTOR, North Carolina macular dystrophy, NCMD, non-coding single-nucleotide variants, SNVs, PRDM13, Retina, STRUCTURAL VARIANTS, Xenopus laevis, Genetics, Medicine and Health Sciences, Animals, Humans, Ccis-regulatory elements, CREswhole-genome sequencing, North Carolina macular dystrophy, Genetics (clinical), Corneal Dystrophies, Hereditary, NCMD, enhanceropathy, Biology and Life Sciences, TRANSGENESIS, multi-omics, GENE, DUPLICATION, UMI-4, Pedigree, FAMILY, GENOME, cis-regulatory elements, CREs, whole-genome sequencing, cis-regulatory elements, UMI-4C, CREs, non-coding single-nucleotide variants, SNVs, Human medicine, human retina, Tomography, Optical Coherence, IRX1
Abstract

North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 promoters and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays. Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two NCMD-associated non-coding SNVs that we identified herein. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, suggesting that this region is a PRDM13 enhancer. Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis. Overall, this study provides insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy., This work was supported by grants from Ghent University Special Research Fund (BOF20/GOA/023) (E.D.B., K.V., B.P.L.); Ghent University Hospital Innovation Fund NucleUZ (E.D.B.); JED Foundation (E.D.B.); H2020 Marie Sklodowska-Curie Innovative Training Networks (ITN) StarT (grant No. 813490) (E.D.B., K.V., J.L.G.-S., J.J.T., J.R.M.-M.); EJP RD Solve-RET EJPRD19-234 (E.D.B., P.L.,B.K., C.R., J.L.G.-S., J.J.T., J.R.M.-M.), SNSF grant # 204285 (C.R.), and Foundation Fighting Blindness in Columbia, MD (grant #: BR-GE-1216-0715-CSH). S.V.d.S. (1145719N) is PhD fellow of the Research Foundation Flanders (FWO), E.D.B. (1802220N) and B.P.L. (1803816N) are FWO Senior Clinical Investigators; M.B.C., V.L.S., and A.D.R. are Early Starting Researcher of ITN StarT (grant # 813490). B.K., B.P.L., C.J.F.B., E.D.B., P.L., and V.V. are members of ERN-EYE (Framework Partnership Agreement No 739534-ERNEYE). K.W.S. received an unrestricted grant from The Molecular Insight Research Foundation.

Published
2022
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12. Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models

Author

Mohajeri, Kiana, primary, Yadav, Rachita, additional, D'haene, Eva, additional, Boone, Philip M., additional, Erdin, Serkan, additional, Gao, Dadi, additional, Moyses-Oliveira, Mariana, additional, Bhavsar, Riya, additional, Currall, Benjamin B., additional, O'Keefe, Kathryn, additional, Burt, Nicholas D., additional, Lowther, Chelsea, additional, Lucente, Diane, additional, Salani, Monica, additional, Larson, Mathew, additional, Redin, Claire, additional, Dudchenko, Olga, additional, Aiden, Erez Lieberman, additional, Menten, Björn, additional, Tai, Derek J.C., additional, Gusella, James F., additional, Vergult, Sarah, additional, and Talkowski, Michael E., additional

Published
2022
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14. Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

Author

Ghent University, European Commission, Foundation Fighting Blindness, Research Foundation - Flanders, Sompele, Stijn Van de, Small, Kent W., Burcu Cicekdal, Munevver, López Soriano, Víctor, D’haene, Eva, Shaya, Fadi S., Agemy, Steven, Snickt, Thijs Van der, Dueñas Rey, Alfredo, Rosseel, Toon, Heetvelde, Mattias Van, Vergult, Sarah, Balikova, Irina, Bergen, Arthur A., Boon, Camiel J.F., Zaeytijd, Julie De, Inglehearn, Chris F., Kousal, Bohdan, Leroy, Bart P., Rivolta, Carlo, Vaclavik, Veronika, Ende, Jenneke van den, Schooneveld, Mary J. van, Gómez-Skarmeta, José Luis, Tena, Juan J., Martínez-Morales, Juan Ramón, Liskova, Petra, Vleminckx, Kris, Baere, Elfride De, Ghent University, European Commission, Foundation Fighting Blindness, Research Foundation - Flanders, Sompele, Stijn Van de, Small, Kent W., Burcu Cicekdal, Munevver, López Soriano, Víctor, D’haene, Eva, Shaya, Fadi S., Agemy, Steven, Snickt, Thijs Van der, Dueñas Rey, Alfredo, Rosseel, Toon, Heetvelde, Mattias Van, Vergult, Sarah, Balikova, Irina, Bergen, Arthur A., Boon, Camiel J.F., Zaeytijd, Julie De, Inglehearn, Chris F., Kousal, Bohdan, Leroy, Bart P., Rivolta, Carlo, Vaclavik, Veronika, Ende, Jenneke van den, Schooneveld, Mary J. van, Gómez-Skarmeta, José Luis, Tena, Juan J., Martínez-Morales, Juan Ramón, Liskova, Petra, Vleminckx, Kris, and Baere, Elfride De

Abstract

North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 promoters and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays. Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two NCMD-associated non-coding SNVs that we identified herein. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, suggesting that this region is a PRDM13 enhancer. Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis. Overall, this study provides insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.

Published
2022

15. HDAC9 structural variants disrupting TWIST1 transcriptional regulation lead to craniofacial and limb malformations

Author

Hirsch, Naama, primary, Dahan, Idit, additional, D'haene, Eva, additional, Avni, Matan, additional, Vergult, Sarah, additional, Vidal-García, Marta, additional, Magini, Pamela, additional, Graziano, Claudio, additional, Severi, Giulia, additional, Bonora, Elena, additional, Nardone, Anna Maria, additional, Brancati, Francesco, additional, Fernández-Jaén, Alberto, additional, Rory, Olson J., additional, Hallgrímsson, Benedikt, additional, and Birnbaum, Ramon Y., additional

Published
2022
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18. A novel neurodevelopmental syndrome caused by loss-of-function of the Zinc Finger Homeobox 3 (ZFHX3) gene

Author

Pérez Baca, Maria del Rocio, Jacobs, Eva, Vantomme, Lies, LeBlanc, Pontus, Bogaert, Elke, Dheedene, Annelies, De Cock, Laurenz, Dermaut, Bart, Foroutan, Aidin, Kerkhof, Jennifer, McConkey, Haley, Sadikovic, Bekim, Consortium, ZFHX3, Menten, Björn, Yuan, Bo, Vergult, Sarah, and Callewaert, Bert

Subjects
Medicine and Health Sciences
Abstract

Neurodevelopmental disorders result from impaired development and functioning of the brain. Here, we identify loss-of-function variation in ZFHX3 as a novel cause for syndromic intellectual disability (ID). ZFHX3, previously known as ATBF1, is a zinc-finger homeodomain transcription factor involved in multiple biological processes including cell differentiation and tumorigenesis. Through international collaboration, we collected clinical data of 34 individuals with premature truncating variants or (partial) deletions of ZFHX3. Loss-of-function variation of ZFHX3 consistently associates with (mild) ID, postnatal growth retardation, feeding difficulties, and recognizable facial characteristics as supported by artificial intelligence (Face2Gene). Data-mining and in-house generated expression data show increased nuclear expression of ZFHX3 during human brain development and neuronal differentiation. To identify the direct binding partners of ZFHX3, we performed immunoprecipitation followed by mass spectrometry in neural stem cells and SH-SY5Y. We show that ZFHX3 interacts with the chromatin remodelling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex. In addition, we identified a specific DNA methylation signature in leukocyte-derived DNA. In Drosophila melanogaster, ZFH2 is considered the ZFHX3 orthologue. We used a reverse genetic approach to characterize ZFH2 deficiency in Drosophila melanogaster. ZFH2 is expressed in the third instar larval brain and its knockdown results in an adult lethal phenotype, suggestive for a key role in development. In conclusion, loss-of-function variants in ZFHX3 are a novel cause for syndromic ID and are associated with a specific DNA methylation episignature. Our results indicate a role for ZFHX3 in chromatin remodelling and mRNA processing.

Published
2022

19. A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development

Author

Wilderman, Andrea, primary, D’haene, Eva, additional, Baetens, Machteld, additional, Yankee, Tara N., additional, Winchester, Emma Wentworth, additional, Glidden, Nicole, additional, Roets, Ellen, additional, Van Dorpe, Jo, additional, Vergult, Sarah, additional, Cox, Timothy C., additional, and Cotney, Justin, additional

Published
2022
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20. Multi-omics profiling, in vitro and in vivo enhancer assays dissect the cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

Author

Van de Sompele, Stijn, primary, Small, Kent W., additional, Cicekdal, Munevver Burcu, additional, Soriano, Víctor López, additional, D’haene, Eva, additional, Shaya, Fadi S., additional, Agemy, Steven, additional, Van der Snickt, Thijs, additional, Rey, Alfredo Dueñas, additional, Rosseel, Toon, additional, Van Heetvelde, Mattias, additional, Vergult, Sarah, additional, Balikova, Irina, additional, Bergen, Arthur A., additional, Boon, Camiel J. F., additional, De Zaeytijd, Julie, additional, Inglehearn, Chris F., additional, Kousal, Bohdan, additional, Leroy, Bart P., additional, Rivolta, Carlo, additional, Vaclavik, Veronika, additional, van den Ende, Jenneke, additional, van Schooneveld, Mary J., additional, Gómez-Skarmeta, José Luis, additional, Tena, Juan J., additional, Martinez-Morales, Juan R., additional, Liskova, Petra, additional, Vleminckx, Kris, additional, and De Baere, Elfride, additional

Published
2022
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21. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author

Coursimault, Juliette, primary, Guerrot, Anne-Marie, additional, Morrow, Michelle M., additional, Schramm, Catherine, additional, Zamora, Francisca Millan, additional, Shanmugham, Anita, additional, Liu, Shuxi, additional, Zou, Fanggeng, additional, Bilan, Frédéric, additional, Le Guyader, Gwenaël, additional, Bruel, Ange-Line, additional, Denommé-Pichon, Anne-Sophie, additional, Faivre, Laurence, additional, Tran Mau-Them, Frédéric, additional, Tessarech, Marine, additional, Colin, Estelle, additional, El Chehadeh, Salima, additional, Gérard, Bénédicte, additional, Schaefer, Elise, additional, Cogne, Benjamin, additional, Isidor, Bertrand, additional, Nizon, Mathilde, additional, Doummar, Diane, additional, Valence, Stéphanie, additional, Héron, Delphine, additional, Keren, Boris, additional, Mignot, Cyril, additional, Coutton, Charles, additional, Devillard, Françoise, additional, Alaix, Anne-Sophie, additional, Amiel, Jeanne, additional, Colleaux, Laurence, additional, Munnich, Arnold, additional, Poirier, Karine, additional, Rio, Marlène, additional, Rondeau, Sophie, additional, Barcia, Giulia, additional, Callewaert, Bert, additional, Dheedene, Annelies, additional, Kumps, Candy, additional, Vergult, Sarah, additional, Menten, Björn, additional, Chung, Wendy K., additional, Hernan, Rebecca, additional, Larson, Austin, additional, Nori, Kelly, additional, Stewart, Sarah, additional, Wheless, James, additional, Kresge, Christina, additional, Pletcher, Beth A., additional, Caumes, Roseline, additional, Smol, Thomas, additional, Sigaudy, Sabine, additional, Coubes, Christine, additional, Helm, Margaret, additional, Smith, Rosemarie, additional, Morrison, Jennifer, additional, Wheeler, Patricia G., additional, Kritzer, Amy, additional, Jouret, Guillaume, additional, Afenjar, Alexandra, additional, Deleuze, Jean-François, additional, Olaso, Robert, additional, Boland, Anne, additional, Poitou, Christine, additional, Frebourg, Thierry, additional, Houdayer, Claude, additional, Saugier-Veber, Pascale, additional, Nicolas, Gaël, additional, and Lecoquierre, François, additional

Published
2021
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23. HDAC9structural variants disruptingTWIST1transcriptional regulation lead to craniofacial and limb malformations

Author

Hirsch, Naama, primary, Dahan, Idit, additional, D’haene, Eva, additional, Avni, Matan, additional, Vergult, Sarah, additional, Vidal-García, Marta, additional, Magini, Pamela, additional, Graziano, Claudio, additional, Severi, Giulia, additional, Bonora, Elena, additional, Nardone, Anna Maria, additional, Brancati, Francesco, additional, Fernández-Jaén, Alberto, additional, Rory, Olson J., additional, Hallgrimsson, Benedikt, additional, and Birnbaum, Ramon Y., additional

Published
2021
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24. A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome

Author

Meerschaut, Ilse, primary, Vergult, Sarah, additional, Dheedene, Annelies, additional, Menten, Björn, additional, De Groote, Katya, additional, De Wilde, Hans, additional, Muiño Mosquera, Laura, additional, Panzer, Joseph, additional, Vandekerckhove, Kristof, additional, Coucke, Paul J., additional, De Wolf, Daniël, additional, and Callewaert, Bert, additional

Published
2021
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26. Expanding the Phenotype of B3GALNT2-Related Disorders.

Author

D'haenens, Erika, Vergult, Sarah, Menten, Björn, Dheedene, Annelies, Kooy, R. Frank, and Callewaert, Bert

Subjects
*LIMB-girdle muscular dystrophy, *MUSCULAR dystrophy, *AUTISM spectrum disorders, *PHENOTYPES, *EXOMES, *DEVELOPMENTAL delay
Abstract

Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) that include a broad phenotypic spectrum ranging from late-onset limb-girdle muscular dystrophy to severe muscle–eye–brain disease, Walker–Warburg syndrome, and Fukuyama congenital muscular dystrophy. In addition to clinical heterogeneity, CMDs are characterized by genetic heterogeneity. To date, 18 genes have been associated with CMDs. One of them is B3GALNT2, which encodes the β-1,3-N-acetylgalactosaminyltransferase 2 that glycosylates α-dystroglycan. In this study, using exome sequencing, we identify a homozygous frameshift variant in B3GALNT2 due to a mixed uniparental disomy of chromosome 1 in a 7-year-old girl with global developmental delay, severely delayed active language development, and autism spectrum disorder but without any symptoms of muscular dystrophy. In addition to this case, we also provide an overview of all previously reported cases, further expanding the phenotypic spectrum. [ABSTRACT FROM AUTHOR]

Published
2022
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28. Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants

Author

Jacobs, Eva Z., primary, Brown, Kathleen, additional, Byler, Melissa C., additional, D'haenens, Erika, additional, Dheedene, Annelies, additional, Henderson, Lindsay B., additional, Humberson, Jennifer B., additional, van Jaarsveld, Richard H., additional, Kanani, Farah, additional, Lebel, Robert Roger, additional, Millan, Francisca, additional, Oegema, Renske, additional, Oostra, Ann, additional, Parker, Michael J., additional, Rhodes, Lindsay, additional, Saenz, Margarita, additional, Seaver, Laurie H., additional, Si, Yue, additional, Vanlander, Arnaud, additional, Vergult, Sarah, additional, and Callewaert, Bert, additional

Published
2020
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29. A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett like characteristics

Author

D’haene, Eva, primary, Bar-Yaacov, Reut, additional, Bariah, Inbar, additional, Vantomme, Lies, additional, Van Loo, Sien, additional, Cobos, Francisco Avila, additional, Verboom, Karen, additional, Eshel, Reut, additional, Alatawna, Rawan, additional, Menten, Björn, additional, Birnbaum, Ramon Y, additional, and Vergult, Sarah, additional

Published
2020
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31. HDAC9structural variants disrupting TWIST1transcriptional regulation lead to craniofacial and limb malformations

Author

Hirsch, Naama, Dahan, Idit, D'haene, Eva, Avni, Matan, Vergult, Sarah, Vidal-García, Marta, Magini, Pamela, Graziano, Claudio, Severi, Giulia, Bonora, Elena, Nardone, Anna Maria, Brancati, Francesco, Fernández-Jaén, Alberto, Rory, Olson J., Hallgrímsson, Benedikt, and Birnbaum, Ramon Y.

Abstract

Structural variants (SVs) can affect protein-coding sequences as well as gene regulatory elements. However, SVs disrupting protein-coding sequences that also function as cis-regulatory elements remain largely uncharacterized. Here, we show that craniosynostosis patients with SVs containing the histone deacetylase 9 (HDAC9) protein-coding sequence are associated with disruption of TWIST1regulatory elements that reside within the HDAC9sequence. Based on SVs within the HDAC9‐TWIST1locus, we defined the 3′-HDAC9sequence as a critical TWIST1regulatory region, encompassing craniofacial TWIST1enhancers and CTCF sites. Deletions of either Twist1enhancers (eTw5-7Δ/Δ) or CTCF site (CTCF-5Δ/Δ) within the Hdac9protein-coding sequence led to decreased Twist1expression and altered anterior/posterior limb expression patterns of SHH pathway genes. This decreased Twist1expression results in a smaller sized and asymmetric skull and polydactyly that resembles Twist1+/−mouse phenotype. Chromatin conformation analysis revealed that the Twist1promoter interacts with Hdac9sequences that encompass Twist1enhancers and a CTCF site, and that interactions depended on the presence of both regulatory regions. Finally, a large inversion of the entire Hdac9sequence (Hdac9INV/+) in mice that does not disrupt Hdac9expression but repositions Twist1regulatory elements showed decreased Twist1expression and led to a craniosynostosis-like phenotype and polydactyly. Thus, our study elucidates essential components of TWIST1transcriptional machinery that reside within the HDAC9sequence. It suggests that SVs encompassing protein-coding sequences could lead to a phenotype that is not attributed to its protein function but rather to a disruption of the transcriptional regulation of a nearby gene.

Published
2022
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32. Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants.

Author

Jacobs, Eva Z., Brown, Kathleen, Byler, Melissa C., D'haenens, Erika, Dheedene, Annelies, Henderson, Lindsay B., Humberson, Jennifer B., Jaarsveld, Richard H., Kanani, Farah, Lebel, Robert Roger, Millan, Francisca, Oegema, Renske, Oostra, Ann, Parker, Michael J., Rhodes, Lindsay, Saenz, Margarita, Seaver, Laurie H., Si, Yue, Vanlander, Arnaud, and Vergult, Sarah

Subjects
MOLECULAR spectra, PHENOTYPES, DNA copy number variations, INTELLECTUAL disabilities, DEVELOPMENTAL delay, EXOMES
Abstract

The CAMTA1‐associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome‐based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N‐ and C‐ terminal functional domains. Clinical heterogeneity is observed, but 3′‐terminal variants seem to associate with less pronounced cerebellar dysfunction. [ABSTRACT FROM AUTHOR]

Published
2021
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33. A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics

Author

D’haene, Eva, primary, Bar-Yaacov, Reut, additional, Bariah, Inbar, additional, Vantomme, Lies, additional, Van Loo, Sien, additional, Cobos, Francisco Avila, additional, Verboom, Karen, additional, Eshel, Reut, additional, Alatawna, Rawan, additional, Menten, Björn, additional, Birnbaum, Ramon Y, additional, and Vergult, Sarah, additional

Published
2018
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34. Familial cases of a submicroscopic Xp22.2 deletion: genotype-phenotype correlation in microphthalmia with linear skin defects syndrome

Author

Vergult, Sarah, Leroy, Bart, Claerhout, Ilse, and Menten, Björn

Subjects
Male, MICRODELETION SYNDROME, DERMAL APLASIA, MLS SYNDROME, Lyases, GOLTZ-SYNDROME, X-CHROMOSOME INACTIVATION, X Chromosome Inactivation, Medicine and Health Sciences, Humans, Microphthalmos, MOLECULAR CHARACTERIZATION, Child, Genetic Association Studies, CONGENITAL MICROPHTHALMIA, Chromosomes, Human, X, Comparative Genomic Hybridization, GTPase-Activating Proteins, MIDAS SYNDROME MICROPHTHALMIA, Genetic Diseases, X-Linked, Syndrome, Middle Aged, eye diseases, Pedigree, Skin Abnormalities, C-TYPE SYNTHASE, Female, FEMALE INFANT, Chromosome Deletion, Gene Deletion, Research Article
Abstract

Purpose: Microphthalmia with linear skin defects syndrome (MLS or MIDAS, OMIM #309801) is a rare X-linked male-lethal disorder characterized by microphthalmia or other ocular anomalies and skin lesions limited to the face and neck. However, inter-and intrafamilial variability is high. Here we report a familial case of MLS. Methods: A mother and daughter with MLS underwent a complete ophthalmological examination, and extensive imaging, including anterior segment pictures, corneal topography and keratometry, autofluorescence, infrared reflectance and red free images, as well as spectral-domain optical coherence tomography. The mother also underwent full-field flash electroretinography. In addition, high-resolution array comparative genomic hybridization analysis was performed in both as well as in the maternal grandparents of the proband. Results: Microphthalmia and retinal abnormalities were noted in the proband and the mother, whereas only the mother presented with scars of the typical neonatal linear skin defects. Array comparative genomic hybridization analysis revealed a 185-220 kb deletion on chromosome band Xp22.2 including the entire HCCS gene. Conclusions: The identification of a deletion including HCCS led to the diagnosis of MLS in these patients. Retinal abnormalities can be part of the ocular manifestations of MLS.

Published
2013

35. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, Talkowski, Michael E, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, and Talkowski, Michael E

Published
2017

36. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Genetica Klinische Genetica, Brain, CMM, Circulatory Health, Cancer, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Cuppen, Genetica, CMM Groep Kloosterman, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, Talkowski, Michael E, Genetica Klinische Genetica, Brain, CMM, Circulatory Health, Cancer, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Cuppen, Genetica, CMM Groep Kloosterman, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, and Talkowski, Michael E

Published
2017

38. New insights into the phenotype of FARS2 deficiency

Author

Vantroys, Elise, primary, Larson, Austin, additional, Friederich, Marisa, additional, Knight, Kaz, additional, Swanson, Michael A., additional, Powell, Christopher A., additional, Smet, Joél, additional, Vergult, Sarah, additional, De Paepe, Boel, additional, Seneca, Sara, additional, Roeyers, Herbert, additional, Menten, Björn, additional, Minczuk, Michal, additional, Vanlander, Arnaud, additional, Van Hove, Johan, additional, and Van Coster, Rudy, additional

Published
2017
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40. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

Author

Braun, Daniela A, primary, Rao, Jia, additional, Mollet, Geraldine, additional, Schapiro, David, additional, Daugeron, Marie-Claire, additional, Tan, Weizhen, additional, Gribouval, Olivier, additional, Boyer, Olivia, additional, Revy, Patrick, additional, Jobst-Schwan, Tilman, additional, Schmidt, Johanna Magdalena, additional, Lawson, Jennifer A, additional, Schanze, Denny, additional, Ashraf, Shazia, additional, Ullmann, Jeremy F P, additional, Hoogstraten, Charlotte A, additional, Boddaert, Nathalie, additional, Collinet, Bruno, additional, Martin, Gaëlle, additional, Liger, Dominique, additional, Lovric, Svjetlana, additional, Furlano, Monica, additional, Guerrera, I Chiara, additional, Sanchez-Ferras, Oraly, additional, Hu, Jennifer F, additional, Boschat, Anne-Claire, additional, Sanquer, Sylvia, additional, Menten, Björn, additional, Vergult, Sarah, additional, De Rocker, Nina, additional, Airik, Merlin, additional, Hermle, Tobias, additional, Shril, Shirlee, additional, Widmeier, Eugen, additional, Gee, Heon Yung, additional, Choi, Won-Il, additional, Sadowski, Carolin E, additional, Pabst, Werner L, additional, Warejko, Jillian K, additional, Daga, Ankana, additional, Basta, Tamara, additional, Matejas, Verena, additional, Scharmann, Karin, additional, Kienast, Sandra D, additional, Behnam, Babak, additional, Beeson, Brendan, additional, Begtrup, Amber, additional, Bruce, Malcolm, additional, Ch'ng, Gaik-Siew, additional, Lin, Shuan-Pei, additional, Chang, Jui-Hsing, additional, Chen, Chao-Huei, additional, Cho, Megan T, additional, Gaffney, Patrick M, additional, Gipson, Patrick E, additional, Hsu, Chyong-Hsin, additional, Kari, Jameela A, additional, Ke, Yu-Yuan, additional, Kiraly-Borri, Cathy, additional, Lai, Wai-ming, additional, Lemyre, Emmanuelle, additional, Littlejohn, Rebecca Okashah, additional, Masri, Amira, additional, Moghtaderi, Mastaneh, additional, Nakamura, Kazuyuki, additional, Ozaltin, Fatih, additional, Praet, Marleen, additional, Prasad, Chitra, additional, Prytula, Agnieszka, additional, Roeder, Elizabeth R, additional, Rump, Patrick, additional, Schnur, Rhonda E, additional, Shiihara, Takashi, additional, Sinha, Manish D, additional, Soliman, Neveen A, additional, Soulami, Kenza, additional, Sweetser, David A, additional, Tsai, Wen-Hui, additional, Tsai, Jeng-Daw, additional, Topaloglu, Rezan, additional, Vester, Udo, additional, Viskochil, David H, additional, Vatanavicharn, Nithiwat, additional, Waxler, Jessica L, additional, Wierenga, Klaas J, additional, Wolf, Matthias T F, additional, Wong, Sik-Nin, additional, Leidel, Sebastian A, additional, Truglio, Gessica, additional, Dedon, Peter C, additional, Poduri, Annapurna, additional, Mane, Shrikant, additional, Lifton, Richard P, additional, Bouchard, Maxime, additional, Kannu, Peter, additional, Chitayat, David, additional, Magen, Daniella, additional, Callewaert, Bert, additional, van Tilbeurgh, Herman, additional, Zenker, Martin, additional, Antignac, Corinne, additional, and Hildebrandt, Friedhelm, additional

Published
2017
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42. Implementation of non-invasive prenatal testing by semiconductor sequencing in a genetic laboratory.

Author

UCL - (SLuc) Centre de génétique médicale UCL, Dheedene, Annelies, Sante, Tom, De Smet, Matthias, Vanbellinghen, Jean-François, Grisart, Bernard, Vergult, Sarah, Janssens, Sandra, Menten, Björn, UCL - (SLuc) Centre de génétique médicale UCL, Dheedene, Annelies, Sante, Tom, De Smet, Matthias, Vanbellinghen, Jean-François, Grisart, Bernard, Vergult, Sarah, Janssens, Sandra, and Menten, Björn

Abstract

Objectives: To implement non-invasive prenatal testing (NIPT) for fetal aneuploidies with semiconductor sequencing in an academic cytogenomic laboratory and to evaluate the first 15-month experience on clinical samples. Methods: We validated a NIPT protocol for cell-free fetal DNA sequencing from maternal plasma for the detection of trisomy 13, 18 and 21 on a semiconductor sequencing instrument. Fetal DNA fraction calculation for all samples and several quality parameters were implemented in the workflow. One thousand eighty-one clinical NIPT samples were analysed, following the described protocol. Results: Non-invasive prenatal testing was successfully implemented and validated on 201 normal and 74 aneuploid samples. From 1081 clinical samples, 17 samples showed an abnormal result: 14 trisomy 21 samples, one trisomy 18 and one trisomy 16 were detected. Also a maternal copy number variation on chromosome 13 was observed, which could potentially lead to a false positive trisomy 13 result. One sex discordant result was reported, possibly attributable to a vanishing twin. Moreover, our combined fetal fraction calculation enabled a more reliable risk estimate for trisomy 13, 18 and 21. Conclusions: Non-invasive prenatal testing for trisomy 21, 18 and 13 has a very high specificity and sensitivity. Because of several biological phenomena, diagnostic invasive confirmation of abnormal results remains required.

Published
2016

43. Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination

Author

Coppieters, Frauke, Ascari, Giulia, Dannhausen, Katharina, Nikopoulos, Konstantinos, Peelman, Frank, Karlstetter, Marcus, Xu, Mingchu, Brachet, Cecile, Meunier, Isabelle, Tsilimbaris, Miltiadis K., Tsika, Chrysanthi, Blazaki, Styliani V., Vergult, Sarah, Farinelli, Pietro, Van Laethem, Thalia, Bauwens, Miriam, De Bruyne, Marieke, Chen, Rui, Langmann, Thomas, Sui, Ruifang, Meire, Francoise, Rivolta, Carlo, Hamel, Christian P., Leroy, Bart P., De Baere, Elfride, Coppieters, Frauke, Ascari, Giulia, Dannhausen, Katharina, Nikopoulos, Konstantinos, Peelman, Frank, Karlstetter, Marcus, Xu, Mingchu, Brachet, Cecile, Meunier, Isabelle, Tsilimbaris, Miltiadis K., Tsika, Chrysanthi, Blazaki, Styliani V., Vergult, Sarah, Farinelli, Pietro, Van Laethem, Thalia, Bauwens, Miriam, De Bruyne, Marieke, Chen, Rui, Langmann, Thomas, Sui, Ruifang, Meire, Francoise, Rivolta, Carlo, Hamel, Christian P., Leroy, Bart P., and De Baere, Elfride

Abstract

Inherited retinal dystrophies (iRDs) are a group of genetically and clinically heterogeneous conditions resulting from mutations in over 250 genes. Here, homozygosity mapping and whole-exome sequencing (WES) in a consanguineous family revealed a homozygous missense mutation, c.973C>T (p.His325Tyr), in RCBTB1. In affected individuals, it was found to segregate with retinitis pigmentosa (RP), goiter, primary ovarian insufficiency, and mild intellectual disability. Subsequent analysis of WES data in different cohorts uncovered four additional homozygous missense mutations in five unrelated families in whom iRD segregates with or without syndromic features. Ocular phenotypes ranged from typical RP starting in the second decade to chorioretinal dystrophy with a later age of onset. The five missense mutations affect highly conserved residues either in the sixth repeat of the RCC1 domain or in the BTB1 domain. A founder haplotype was identified for mutation c.919G>A (p.Val307Met), occurring in two families of Mediterranean origin. We showed ubiquitous mRNA expression of RCBTB1 and demonstrated predominant RCBTB1 localization in human inner retina. RCBTB1 was very recently shown to be involved in ubiquitination, more specifically as a CUL3 substrate adaptor. Therefore, the effect on different components of the CUL3 and NFE2L2 (NRF2) pathway was assessed in affected individuals' lymphocytes, revealing decreased mRNA expression of NFE2L2 and several NFE2L2 target genes. In conclusion, our study puts forward mutations in RCBTB1 as a cause of autosomal-recessive non-syndromic and syndromic iRD. Finally, our data support a role for impaired ubiquitination in the pathogenetic mechanism of RCBTB1 mutations.

Published
2016

44. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Redin, Claire, primary, Brand, Harrison, additional, Collins, Ryan L, additional, Kammin, Tammy, additional, Mitchell, Elyse, additional, Hodge, Jennelle C, additional, Hanscom, Carrie, additional, Pillalamarri, Vamsee, additional, Seabra, Catarina M, additional, Abbott, Mary-Alice, additional, Abdul-Rahman, Omar A, additional, Aberg, Erika, additional, Adley, Rhett, additional, Alcaraz-Estrada, Sofia L, additional, Alkuraya, Fowzan S, additional, An, Yu, additional, Anderson, Mary-Anne, additional, Antolik, Caroline, additional, Anyane-Yeboa, Kwame, additional, Atkin, Joan F, additional, Bartell, Tina, additional, Bernstein, Jonathan A, additional, Beyer, Elizabeth, additional, Blumenthal, Ian, additional, Bongers, Ernie M H F, additional, Brilstra, Eva H, additional, Brown, Chester W, additional, Brüggenwirth, Hennie T, additional, Callewaert, Bert, additional, Chiang, Colby, additional, Corning, Ken, additional, Cox, Helen, additional, Cuppen, Edwin, additional, Currall, Benjamin B, additional, Cushing, Tom, additional, David, Dezso, additional, Deardorff, Matthew A, additional, Dheedene, Annelies, additional, D'Hooghe, Marc, additional, de Vries, Bert B A, additional, Earl, Dawn L, additional, Ferguson, Heather L, additional, Fisher, Heather, additional, FitzPatrick, David R, additional, Gerrol, Pamela, additional, Giachino, Daniela, additional, Glessner, Joseph T, additional, Gliem, Troy, additional, Grady, Margo, additional, Graham, Brett H, additional, Griffis, Cristin, additional, Gripp, Karen W, additional, Gropman, Andrea L, additional, Hanson-Kahn, Andrea, additional, Harris, David J, additional, Hayden, Mark A, additional, Hill, Rosamund, additional, Hochstenbach, Ron, additional, Hoffman, Jodi D, additional, Hopkin, Robert J, additional, Hubshman, Monika W, additional, Innes, A Micheil, additional, Irons, Mira, additional, Irving, Melita, additional, Jacobsen, Jessie C, additional, Janssens, Sandra, additional, Jewett, Tamison, additional, Johnson, John P, additional, Jongmans, Marjolijn C, additional, Kahler, Stephen G, additional, Koolen, David A, additional, Korzelius, Jerome, additional, Kroisel, Peter M, additional, Lacassie, Yves, additional, Lawless, William, additional, Lemyre, Emmanuelle, additional, Leppig, Kathleen, additional, Levin, Alex V, additional, Li, Haibo, additional, Li, Hong, additional, Liao, Eric C, additional, Lim, Cynthia, additional, Lose, Edward J, additional, Lucente, Diane, additional, Macera, Michael J, additional, Manavalan, Poornima, additional, Mandrile, Giorgia, additional, Marcelis, Carlo L, additional, Margolin, Lauren, additional, Mason, Tamara, additional, Masser-Frye, Diane, additional, McClellan, Michael W, additional, Mendoza, Cinthya J Zepeda, additional, Menten, Björn, additional, Middelkamp, Sjors, additional, Mikami, Liya R, additional, Moe, Emily, additional, Mohammed, Shehla, additional, Mononen, Tarja, additional, Mortenson, Megan E, additional, Moya, Graciela, additional, Nieuwint, Aggie W, additional, Ordulu, Zehra, additional, Parkash, Sandhya, additional, Pauker, Susan P, additional, Pereira, Shahrin, additional, Perrin, Danielle, additional, Phelan, Katy, additional, Aguilar, Raul E Piña, additional, Poddighe, Pino J, additional, Pregno, Giulia, additional, Raskin, Salmo, additional, Reis, Linda, additional, Rhead, William, additional, Rita, Debra, additional, Renkens, Ivo, additional, Roelens, Filip, additional, Ruliera, Jayla, additional, Rump, Patrick, additional, Schilit, Samantha L P, additional, Shaheen, Ranad, additional, Sparkes, Rebecca, additional, Spiegel, Erica, additional, Stevens, Blair, additional, Stone, Matthew R, additional, Tagoe, Julia, additional, Thakuria, Joseph V, additional, van Bon, Bregje W, additional, van de Kamp, Jiddeke, additional, van Der Burgt, Ineke, additional, van Essen, Ton, additional, van Ravenswaaij-Arts, Conny M, additional, van Roosmalen, Markus J, additional, Vergult, Sarah, additional, Volker-Touw, Catharina M L, additional, Warburton, Dorothy P, additional, Waterman, Matthew J, additional, Wiley, Susan, additional, Wilson, Anna, additional, Yerena-de Vega, Maria de la Concepcion A, additional, Zori, Roberto T, additional, Levy, Brynn, additional, Brunner, Han G, additional, de Leeuw, Nicole, additional, Kloosterman, Wigard P, additional, Thorland, Erik C, additional, Morton, Cynthia C, additional, Gusella, James F, additional, and Talkowski, Michael E, additional

Published
2016
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45. Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1 , a Gene Implicated in Ubiquitination

Author

Coppieters, Frauke, primary, Ascari, Giulia, additional, Dannhausen, Katharina, additional, Nikopoulos, Konstantinos, additional, Peelman, Frank, additional, Karlstetter, Marcus, additional, Xu, Mingchu, additional, Brachet, Cécile, additional, Meunier, Isabelle, additional, Tsilimbaris, Miltiadis K., additional, Tsika, Chrysanthi, additional, Blazaki, Styliani V., additional, Vergult, Sarah, additional, Farinelli, Pietro, additional, Van Laethem, Thalia, additional, Bauwens, Miriam, additional, De Bruyne, Marieke, additional, Chen, Rui, additional, Langmann, Thomas, additional, Sui, Ruifang, additional, Meire, Françoise, additional, Rivolta, Carlo, additional, Hamel, Christian P., additional, Leroy, Bart P., additional, and De Baere, Elfride, additional

Published
2016
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48. Two siblings with homozygous pathogenic splice-site variant in mitochondrial asparaginyl-tRNA synthetase (NARS2)

Author

Vanlander, Arnaud Vincent, Smet, Joel, De Paepe, Boel, De Latter, Elien, Van Coster, Rudy, Menten, Björn, Sante, Tom, Vergult, Sarah, Vantomme, Lies, De Meirleir, Linda, Seneca, Sara, Pearce, Sarah S.F., Powell, Christopher C.A., Minczuk, Michal, Michotte, Alex, Vanlander, Arnaud Vincent, Smet, Joel, De Paepe, Boel, De Latter, Elien, Van Coster, Rudy, Menten, Björn, Sante, Tom, Vergult, Sarah, Vantomme, Lies, De Meirleir, Linda, Seneca, Sara, Pearce, Sarah S.F., Powell, Christopher C.A., Minczuk, Michal, and Michotte, Alex

Abstract

A homozygous missense mutation (c.822G>C) was found in the gene encoding the mitochondrial asparaginyl-tRNA synthetase (NARS2) in two siblings born to consanguineous parents. These siblings presented with different phenotypes: one had mild intellectual disability and epilepsy in childhood, whereas the other had severe myopathy. Biochemical analysis of the oxidative phosphorylation (OXPHOS) complexes in both siblings revealed a combined complex I and IV deficiency in skeletal muscle. In-gel activity staining after blue native-polyacrylamide gel electrophoresis confirmed the decreased activity of complex I and IV, and, in addition, showed the presence of complex V subcomplexes. Considering the consanguineous descent, homozygosity mapping and whole-exome sequencing were combined revealing the presence of one single missense mutation in the shared homozygous region. The c.822G>C variant affects the 3′ splice site of exon 7, leading to skipping of the whole exon 7 and a part of exon 8 in the NARS2 mRNA. In EBV-transformed lymphoblasts, a specific decrease in the amount of charged mt-tRNAAsn was demonstrated as compared with controls. This confirmed the pathogenic nature of the variant. To conclude, the reported variant in NARS2 results in a combined OXPHOS complex deficiency involving complex I and IV, making NARS2 a new member of disease-associated aaRS2., SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

Published
2015

49. Refinement of the critical 2p25.3 deletion region:the role of MYT1L in intellectual disability and obesity

Author

De Rocker, Nina, Vergult, Sarah, Koolen, David, Jacobs, Eva, Hoischen, Alexander, Zeesman, Susan, Bang, Birgitte, Béna, Frédérique, Bockaert, Nele, Bongers, Ernie M, de Ravel, Thomy, Devriendt, Koenraad, Giglio, Sabrina, Faivre, Laurence, Joss, Shelagh, Maas, Saskia, Marle, Nathalie, Novara, Francesca, Nowaczyk, Malgorzata J M, Peeters, Hilde, Polstra, Abeltje, Roelens, Filip, Rosenberg, Carla, Thevenon, Julien, Tümer, Zeynep, Vanhauwaert, Suzanne, Varvagiannis, Konstantinos, Willaert, Andy, Willemsen, Marjolein, Willems, Marjolaine, Zuffardi, Orsetta, Coucke, Paul, Speleman, Frank, Eichler, Evan E, Kleefstra, Tjitske, Menten, Björn, De Rocker, Nina, Vergult, Sarah, Koolen, David, Jacobs, Eva, Hoischen, Alexander, Zeesman, Susan, Bang, Birgitte, Béna, Frédérique, Bockaert, Nele, Bongers, Ernie M, de Ravel, Thomy, Devriendt, Koenraad, Giglio, Sabrina, Faivre, Laurence, Joss, Shelagh, Maas, Saskia, Marle, Nathalie, Novara, Francesca, Nowaczyk, Malgorzata J M, Peeters, Hilde, Polstra, Abeltje, Roelens, Filip, Rosenberg, Carla, Thevenon, Julien, Tümer, Zeynep, Vanhauwaert, Suzanne, Varvagiannis, Konstantinos, Willaert, Andy, Willemsen, Marjolein, Willems, Marjolaine, Zuffardi, Orsetta, Coucke, Paul, Speleman, Frank, Eichler, Evan E, Kleefstra, Tjitske, and Menten, Björn

Abstract

PURPOSE: Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis.METHODS: In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization.RESULTS: Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain.CONCLUSION: Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460-466.

Published
2015

50. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

Author

De Rocker, Nina, primary, Vergult, Sarah, additional, Koolen, David, additional, Jacobs, Eva, additional, Hoischen, Alexander, additional, Zeesman, Susan, additional, Bang, Birgitte, additional, Béna, Frédérique, additional, Bockaert, Nele, additional, Bongers, Ernie M., additional, de Ravel, Thomy, additional, Devriendt, Koenraad, additional, Giglio, Sabrina, additional, Faivre, Laurence, additional, Joss, Shelagh, additional, Maas, Saskia, additional, Marle, Nathalie, additional, Novara, Francesca, additional, Nowaczyk, Malgorzata J.M., additional, Peeters, Hilde, additional, Polstra, Abeltje, additional, Roelens, Filip, additional, Rosenberg, Carla, additional, Thevenon, Julien, additional, Tümer, Zeynep, additional, Vanhauwaert, Suzanne, additional, Varvagiannis, Konstantinos, additional, Willaert, Andy, additional, Willemsen, Marjolein, additional, Willems, Marjolaine, additional, Zuffardi, Orsetta, additional, Coucke, Paul, additional, Speleman, Frank, additional, Eichler, Evan E., additional, Kleefstra, Tjitske, additional, and Menten, Björn, additional

Published
2015
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