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2. The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56.

Author

Almoallem, Basamat, Arno, Gavin, De Zaeytijd, Julie, Verdin, Hannah, Balikova, Irina, Casteels, Ingele, de Ravel, Thomy, Hull, Sarah, Suzani, Martina, Destrée, Anne, Peng, Michelle, Williams, Denise, Ainsworth, John R, Webster, Andrew R, Leroy, Bart P, Moore, Anthony T, and De Baere, Elfride

Subjects
Humans, Microphthalmos, Membrane Proteins, Cohort Studies, Family, Heterozygote, Mutation, Alleles, Adolescent, Adult, Aged, Middle Aged, Child, Child, Preschool, Female, Male, DNA Copy Number Variations, Serine Proteases, Whole Genome Sequencing
Abstract

This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from different ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), five of which are novel including a deletion spanning the 5' untranslated region and the first coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identified in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the first MFRP genomic rearrangement, offering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO.

Published
2020

3. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Abbott, Kristin M., Banka, Siddharth, de Boer, Elke, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Gilissen, Christian, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jackson, Adam, Kerstjens, Mieke, Kleefstra, Tjitske, Martín, Estrella López, Macek, Milan, Jr., Matalonga, Leslie, Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca C., Renieri, Alessandra, Riess, Olaf, Rooryck, Caroline, Ryba, Lukas, Agathe, Jean-Madeleine de Sainte, Santen, Gijs W.E., Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Trimouille, Aurélien, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Zguro, Kristina, Boer, Elke de, Cohen, Enzo, Danis, Daniel, Gao, Fei, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, te Paske, Iris B.A.W., Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vandrovcova, Jana, Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, ‘t Hoen, Peter A.C., Vissers, Lisenka E.L.M., Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, Paske, Iris te, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Alexander, Elizabeth, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Ben Yaou, Rabah, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Efthymiou, Stephanie, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Varavallo, Alessandra, Banfi, Sandro, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Kerstjens Frederikse, Wilhemina S., Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, Lacombe, Didier, Trimouille, Aurelien, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Hackman, Peter, Udd, Bjarne, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Osorio, Andrés Nascimento, Depienne, Christel, Roos, Andreas, Cordts, Isabell, Deschauer, Marcus, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Başak, Ayşe Nazlı, Claeys, Kristl, Boztug, Kaan, Haimel, Matthias, W.E, Gijs, Ruivenkamp, Claudia A.L., Natera de Benito, Daniel, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Radio, Francesca Clementina, Balicza, Peter, Molnar, Maria Judit, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Delgado, Beatriz Martínez, Alonso García de la Rosa, F. Javier, Schröck, Evelin, Rump, Andreas, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Chinnery, Patrick F., Ratnaike, Thiloka, Schon, Katherine, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, May, Patrick, Beeson, David, Cossins, Judith, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Afenjar, Alexandra, Goldenberg, Alice, Masurel, Alice, Phan, Alice, Dieux-Coeslier, Anne, Fargeot, Anne, Guerrot, Anne-Marie, Toutain, Annick, Molin, Arnaud, Sorlin, Arthur, Putoux, Audrey, Jouret, Béatrice, Laudier, Béatrice, Demeer, Bénédicte, Doray, Bérénice, Bonniaud, Bertille, Isidor, Bertrand, Gilbert-Dussardier, Brigitte, Leheup, Bruno, Reversade, Bruno, Paul, Carle, Vincent-Delorme, Catherine, Neiva, Cecilia, Poirsier, Céline, Quélin, Chloé, Chiaverini, Christine, Coubes, Christine, Francannet, Christine, Colson, Cindy, Desplantes, Claire, Wells, Constance, Goizet, Cyril, Sanlaville, Damien, Amram, Daniel, Lehalle, Daphné, Geneviève, David, Gaillard, Dominique, Zivi, Einat, Sarrazin, Elisabeth, Steichen, Elisabeth, Schaefer, Élise, Lacaze, Elodie, Jacquemin, Emmanuel, Bongers, Ernie, Kilic, Esra, Colin, Estelle, Giuliano, Fabienne, Prieur, Fabienne, Laffargue, Fanny, Morice-Picard, Fanny, Petit, Florence, Cartault, François, Feillet, François, Baujat, Geneviève, Morin, Gilles, Diene, Gwenaëlle, Journel, Hubert, Perthus, Isabelle, Lespinasse, James, Alessandri, Jean-Luc, Amiel, Jeanne, Martinovic, Jelena, Delanne, Julian, Albuisson, Juliette, Lambert, Laëtitia, Perrin, Laurence, Ousager, Lilian Bomme, Van Maldergem, Lionel, Pinson, Lucile, Ruaud, Lyse, Samimi, Mahtab, Bournez, Marie, Bonnet-Dupeyron, Marie Noëlle, Vincent, Marie, Jacquemont, Marie-Line, Cordier-Alex, Marie-Pierre, Gérard-Blanluet, Marion, Willems, Marjolaine, Spodenkiewicz, Marta, Doco-Fenzy, Martine, Rossi, Massimiliano, Renaud, Mathilde, Fradin, Mélanie, Mathieu, Michèle, Holder-Espinasse, Muriel H., Houcinat, Nada, Hanna, Nadine, Leperrier, Nathalie, Chassaing, Nicolas, Philip, Nicole, Boute, Odile, Van Kien, Philippe Khau, Parent, Philippe, Bitoun, Pierre, Sarda, Pierre, Vabres, Pierre, Jouk, Pierre-Simon, Touraine, Renaud, El Chehadeh, Salima, Whalen, Sandra, Marlin, Sandrine, Passemard, Sandrine, Grotto, Sarah, Bellanger, Séverine Audebert, Blesson, Sophie, Nambot, Sophie, Naudion, Sophie, Lyonnet, Stanislas, Odent, Sylvie, Attie-Bitach, Tania, Busa, Tiffany, Drouin-Garraud, Valérie, Layet, Valérie, Bizaoui, Varoona, Cusin, Véronica, Capri, Yline, Alembik, Yves, Jean-Marçais, Nolwenn, López-Martín, Estrella, Macek, Milan, Mencarelli, Maria Antonietta, Moutton, Sébastien, Pfundt, Rolph, Safraou, Hana, Thauvin-Robinet, Christel, Thevenon, Julien, Tran Mau-Them, Frédéric, de Vries, Bert B.A., Willemsen, Marjolein H., and Philippe, Christophe

Published
2023
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5. Biallelic RXFP2 variants lead to congenital bilateral cryptorchidism and male infertility, supporting a role of RXFP2 in spermatogenesis.

Author

Syryn, Hannes, Velde, Julie Van de, Clercq, Griet De, Verdin, Hannah, Dheedene, Annelies, Peelman, Frank, Sinclair, Andrew, Ayers, Katie L, Bathgate, Ross A D, Cools, Martine, and Baere, Elfride De

Subjects
MALE infertility, CYCLIC adenylic acid, MISSENSE mutation, FETAL development, REPORTER genes, SPERMATOGENESIS
Abstract

STUDY QUESTION Does RXFP2 disruption impair male fertility? SUMMARY ANSWER We identified biallelic variants in RXFP2 in patients with male infertility due to spermatogenic arrest at the spermatid stage, supporting a role of RXFP2 in human spermatogenesis, specifically in germ cell maturation. WHAT IS KNOWN ALREADY Since RXFP2, the receptor for INSL3, plays a crucial role in testicular descent during prenatal development, biallelic variants lead to bilateral cryptorchidism, as described in four families to date. While animal models have also suggested a function in spermatogenesis, the postnatal functions of RXFP2 and its ligand INSL3, produced in large amounts by the testes from puberty throughout adulthood, are largely unknown. STUDY DESIGN, SIZE, DURATION A family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism underwent clinical, endocrinological, histological, genomic, in vitro cellular, and in silico investigations. PARTICIPANTS/MATERIALS, SETTING, METHODS The endocrinological and histological findings were correlated with publicly available single-cell RNA sequencing (scRNA-seq) data. The genomic defects have been characterized using long-read sequencing and validated with in silico modeling and an in vitro cyclic AMP reporter gene assay. MAIN RESULTS AND THE ROLE OF CHANCE An intragenic deletion of exon 1–5 of RXFP2 (NM_130806.5) was detected in trans with a hemizygous missense variant c.229G>A, p.(Glu77Lys). The p.(Glu77Lys) variant caused no clear change in cell surface expression or ability to bind INSL3, but displayed absence of a cAMP signal in response to INSL3, indicating a loss-of-function. Testicular biopsy in the proband showed a maturation arrest at the spermatid stage, corresponding to the highest level of RXFP2 expression in scRNA-seq data, thereby providing a potential explanation for the impaired fertility. LIMITATIONS, REASONS FOR CAUTION Although this is so far the only study of human cases that supports the role of RXFP2 in spermatogenic maturation, this is corroborated by several animal studies that have already demonstrated a postnatal function of INSL3 and RXFP2 in spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS This study corroborates RXFP2 as gene implicated in autosomal recessive congenital bilateral cryptorchidism due to biallelic variants, rather than autosomal-dominant cryptorchidism due to monoallelic RXFP2 variants. Our findings also support that RXFP2 is essential in human spermatogenesis, specifically in germ cell maturation, and that biallelic disruption can cause male infertility through spermatogenic arrest at the spermatid stage. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by the Bellux Society for Pediatric Endocrinology and Diabetology (BELSPEED) and supported by a Research Foundation Flanders (FWO) senior clinical investigator grant (E.D.B. 1802220N) and a Ghent University Hospital Special Research Fund grant (M.C. FIKO-IV institutional fund). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Shortcutting the diagnostic odyssey: the multidisciplinary Program for Undiagnosed Rare Diseases in adults (UD-PrOZA)

Author

Schuermans, Nika, Hemelsoet, Dimitri, Terryn, Wim, Steyaert, Sanne, Van Coster, Rudy, Coucke, Paul J., Steyaert, Wouter, Callewaert, Bert, Bogaert, Elke, Verloo, Patrick, Vanlander, Arnaud V., Debackere, Elke, Ghijsels, Jody, LeBlanc, Pontus, Verdin, Hannah, Naesens, Leslie, Haerynck, Filomeen, Callens, Steven, Dermaut, Bart, and Poppe, Bruce

Published
2022
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8. Insight into the role of TXNRD2 in steroidogenesis through a novel homozygous TXNRD2 splice variant.

Author

Brachet, Cécile, Laemmle, Alexander, Cools, Martine, Sauter, Kay-Sara, Baere, Elfride De, Vanlander, Arnaud, Pandey, Amit V, Toit, Therina du, Voegel, Clarissa D, Heinrichs, Claudine, Verdin, Hannah, and Flück, Christa E

Subjects
FLAVIN adenine dinucleotide, AMINO acid analysis, PLURIPOTENT stem cells, STRUCTURAL frame models, REACTIVE oxygen species
Abstract

Objective Adrenal cortisol production occurs through a biosynthetic pathway which depend on NADH and NADPH for energy supply. The mitochondrial respiratory chain and the reactive oxygen species (ROS) detoxification system are therefore important for steroidogenesis. Mitochondrial dysfunction leading to oxidative stress has been implicated in the pathogenesis of several adrenal conditions. Nonetheless, only very few patients with variants in one gene of the ROS detoxification system, Thioredoxin Reductase 2 (TXNRD2), have been described with variable phenotypes. Design Clinical, genetic, structural, and functional characterization of a novel, biallelic TXNRD2 splice variant. Methods On human biomaterial, we performed whole exome sequencing to identify and RNA analysis to characterize the specific TXNRD2 splice variant. Amino acid conservation analysis and protein structure modeling were performed in silico. Using patient's fibroblast-derived human induced pluripotent stem cells, we generated adrenal-like cells (iALC) to study the impact of wild-type (WT) and mutant TXNRD2 on adrenal steroidogenesis and ROS production. Results The patient had a complex phenotype of primary adrenal insufficiency (PAI), combined with genital, ophthalmological, and neurological features. He carried a homozygous splice variant c.1348-1G > T in TXNRD2 which leads to a shorter protein lacking the C-terminus and thereby affecting homodimerization and flavin adenine dinucleotide binding. Patient-derived iALC showed a loss of cortisol production with overall diminished adrenal steroidogenesis, while ROS production was significantly increased. Conclusion Lack of TXNRD2 activity for mitochondrial ROS detoxification affects adrenal steroidogenesis and predominantly cortisol production. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Spleen function is reduced in individuals with NR5A1 variants with or without DSD: a cross-sectional study

Author

Cools, Martine, primary, Grijp, Celien, additional, Neirinck, Jana, additional, Tavernier, Simon J, additional, Schelstraete, Petra, additional, Van De Velde, Julie, additional, Morbée, Lieve, additional, De Baere, Elfride, additional, Bonroy, Carolien, additional, van Bever, Yolande, additional, Bruggenwirth, Hennie, additional, Vermont, Clementien, additional, Hannema, Sabine E, additional, De Rijke, Yolanda, additional, Abdulhadi-Atwan, Maha, additional, Zangen, David, additional, Verdin, Hannah, additional, and Haerynck, Filomeen, additional

Published
2023
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12. Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease

Author

Van de Sompele, Stijn, Smith, Claire, Karali, Marianthi, Corton, Marta, Van Schil, Kristof, Peelman, Frank, Cherry, Timothy, Rosseel, Toon, Verdin, Hannah, Derolez, Julien, Van Laethem, Thalia, Khan, Kamron N., McKibbin, Martin, Toomes, Carmel, Ali, Manir, Torella, Annalaura, Testa, Francesco, Jimenez, Belen, Simonelli, Francesca, De Zaeytijd, Julie, Van den Ende, Jenneke, Leroy, Bart P., Coppieters, Frauke, Ayuso, Carmen, Inglehearn, Chris F., Banfi, Sandro, and De Baere, Elfride

Published
2019
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14. Paediatric cataract surgery with 27G vitrectomy instrumentation: the Ghent University Hospital Experience

Author

Chan, Hwei Wuen, primary, Van den Broeck, Filip, additional, Cools, Axelle, additional, Walraedt, Sophie, additional, Joniau, Inge, additional, Verdin, Hannah, additional, Balikova, Irina, additional, Van Nuffel, Stefaan, additional, Delbeke, Patricia, additional, De Baere, Elfride, additional, Leroy, Bart P., additional, and Nerinckx, Fanny, additional

Published
2023
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15. Spleen function is reduced in individuals with NR5A1 variants with or without a difference of sex development: a cross-sectional study.

Author

Cools, Martine, Grijp, Celien, Neirinck, Jana, Tavernier, Simon J, Schelstraete, Petra, Velde, Julie Van De, Morbée, Lieve, Baere, Elfride De, Bonroy, Carolien, Bever, Yolande van, Bruggenwirth, Hennie, Vermont, Clementien, Hannema, Sabine E, Rijke, Yolanda De, Abdulhadi-Atwan, Maha, Zangen, David, Verdin, Hannah, and Haerynck, Filomeen

Subjects
ENDOCRINOLOGY, SEX differentiation disorders, SPLEEN, GONADAL diseases, ASPLENIA, HYPERSPLENISM
Abstract

Objective NR5A1 is a key regulator of sex differentiation and has been implicated in spleen development through transcription activation of TLX1. Concerns exist about hypo- or asplenism in individuals who have a difference of sex development (DSD) due to an NR5A1 disease-causing variant. We aimed to assess spleen anatomy and function in a clinical cohort of such individuals and in their asymptomatic family member carriers. Design Cross-sectional assessment in 22 patients with a DSD or primary ovarian insufficiency and 5 asymptomatic carriers from 18 families, harboring 14 different NR5A1 variants. Methods Spleen anatomy was assessed by ultrasound, spleen function by peripheral blood cell count, white blood cell differentiation, percentage of nonswitched memory B cells, specific pneumococcal antibody response, % pitted red blood cells, and Howell–Jolly bodies. Results Patients and asymptomatic heterozygous individuals had significantly decreased nonswitched memory B cells compared to healthy controls, but higher than asplenic patients. Thrombocytosis and spleen hypoplasia were present in 50% of heterozygous individuals. Four out of 5 individuals homozygous for the previously described p.(Arg103Gln) variant had asplenia. Conclusions Individuals harboring a heterozygous NR5A1 variant that may cause DSD have a considerable risk for functional hyposplenism, irrespective of their gonadal phenotype. Splenic function should be assessed in these individuals, and if affected or unknown, prophylaxis is recommended to prevent invasive encapsulated bacterial infections. The splenic phenotype associated with NR5A1 variants is more severe in homozygous individuals and is, at least for the p.(Arg103Gln) variant, associated with asplenism. [ABSTRACT FROM AUTHOR]

Published
2024
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16. A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

Author

Rosain, Jérémie, Oleaga-Quintas, Carmen, Deswarte, Caroline, Verdin, Hannah, Marot, Stéphane, Syridou, Garyfallia, Mansouri, Mahboubeh, Mahdaviani, S. Alireza, Venegas-Montoya, Edna, Tsolia, Maria, Mesdaghi, Mehrnaz, Chernyshova, Liudmyla, Stepanovskiy, Yuriy, Parvaneh, Nima, Mansouri, Davood, Pedraza-Sánchez, Sigifredo, Bondarenko, Anastasia, Espinosa-Padilla, Sara E., Yamazaki-Nakashimada, Marco A., Nieto-Patlán, Alejandro, Kerner, Gaspard, Lambert, Nathalie, Jacques, Corinne, Corvilain, Emilie, Migaud, Mélanie, Grandin, Virginie, Herrera, María T., Jabot-Hanin, Fabienne, Boisson-Dupuis, Stéphanie, Picard, Capucine, Nitschke, Patrick, Puel, Anne, Tores, Frederic, Abel, Laurent, Blancas-Galicia, Lizbeth, De Baere, Elfride, Bole-Feysot, Christine, Casanova, Jean-Laurent, and Bustamante, Jacinta

Published
2018
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17. Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Author

Baetens, Dorien, Güran, Tülay, Mendonca, Berenice B, Gomes, Nathalia L, De Cauwer, Lode, Peelman, Frank, Verdin, Hannah, Vuylsteke, Marnik, Van der Linden, Malaïka, ESR2 STUDY GROUP, Atay, Zeynep, Bereket, Abdullah, de Krijger, Ronald R, Preter, Katleen de, Domenice, Sorahia, Turan, Serap, Stoop, Hans, Looijenga, Leendert H, De Bosscher, Karolien, Cools, Martine, and De Baere, Elfride

Published
2018
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18. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Denommé-Pichon, Anne-Sophie, Matalonga, Leslie, de Boer, Elke, Jackson, Adam, Benetti, Elisa, Banka, Siddharth, Bruel, Ange-Line, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Duffourd, Yannis, Ellwanger, Kornelia, Fallerini, Chiara, Gilissen, Christian, Graessner, Holm, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jean-Marçais, Nolwenn, Kleefstra, Tjitske, López-Martín, Estrella, Macek, Milan, Mencarelli, Maria Antonietta, Moutton, Sébastien, Pfundt, Rolph, Pizzi, Simone, Posada, Manuel, Radio, Francesca Clementina, Renieri, Alessandra, Rooryck, Caroline, Ryba, Lukas, Safraou, Hana, Schwarz, Martin, Tartaglia, Marco, Thauvin-Robinet, Christel, Thevenon, Julien, Tran Mau-Them, Frédéric, Trimouille, Aurélien, Votypka, Pavel, de Vries, Bert B. A., Willemsen, Marjolein H., Zurek, Birte, Verloes, Alain, Philippe, Christophe, Abbott, Kristin M., Faivre, Laurence, Kerstjens, Mieke, Martín, Estrella López, Macek Jr., Milan, Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Pinelli, Michele, Radio, Francesca C., Riess, Olaf, Agathe, Jean-Madeleine De Sainte, Santen, Gijs W. E., Thauvin, Christel, Torella, Annalaura, Vissers, Lisenka, Vitobello, Antonio, Zguro, Kristina, Boer, Elke De, Cohen, Enzo, Danis, Daniel, Gao, Fei, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, te Paske, Iris B. A. W., Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vandrovcova, Jana, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, `t Hoen, Peter A. C., Vissers, Lisenka E. L. M., Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, Paske, Iris Te, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Alexander, Elizabeth, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Ben Yaou, Rabah, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Li\vsková, Petra, Dole\vzalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Efthymiou, Stephanie, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Varavallo, Alessandra, Banfi, Sandro, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Kerstjens Frederikse, Wilhemina S., Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, Lacombe, Didier, Trimouille, Aurelien, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Hackman, Peter, Udd, Bjarne, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Osorio, Andrés Nascimento, Depienne, Christel, Roos, Andreas, Cordts, Isabell, Deschauer, Marcus, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Claeys, Kristl, Boztug, Kaan, Haimel, Matthias, W.E, Gijs, Ruivenkamp, Claudia A. L., Natera de Benito, Daniel, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Balicza, Peter, Molnar, Maria Judit, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Delgado, Beatriz Martínez, Alonso García de la Rosa, F. Javier, Schröck, Evelin, Rump, Andreas, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Chinnery, Patrick F., Ratnaike, Thiloka, Schon, Katherine, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, May, Patrick, Beeson, David, Cossins, Judith, Furini, Simone, Afenjar, Alexandra, Goldenberg, Alice, Masurel, Alice, Phan, Alice, Dieux-Coeslier, Anne, Fargeot, Anne, Guerrot, Anne-Marie, Toutain, Annick, Molin, Arnaud, Sorlin, Arthur, Putoux, Audrey, Jouret, Béatrice, Laudier, Béatrice, Demeer, Bénédicte, Doray, Bérénice, Bonniaud, Bertille, Isidor, Bertrand, Gilbert-Dussardier, Brigitte, Leheup, Bruno, Reversade, Bruno, Paul, Carle, Vincent-Delorme, Catherine, Neiva, Cecilia, Poirsier, Céline, Quélin, Chloé, Chiaverini, Christine, Coubes, Christine, Francannet, Christine, Colson, Cindy, Desplantes, Claire, Wells, Constance, Goizet, Cyril, Sanlaville, Damien, Amram, Daniel, Lehalle, Daphné, Geneviève, David, Gaillard, Dominique, Zivi, Einat, Sarrazin, Elisabeth, Steichen, Elisabeth, Schaefer, Élise, Lacaze, Elodie, Jacquemin, Emmanuel, Bongers, Ernie, Kilic, Esra, Colin, Estelle, Giuliano, Fabienne, Prieur, Fabienne, Laffargue, Fanny, Morice-Picard, Fanny, Petit, Florence, Cartault, François, Feillet, François, Baujat, Geneviève, Morin, Gilles, Diene, Gwenaëlle, Journel, Hubert, Perthus, Isabelle, Lespinasse, James, Alessandri, Jean-Luc, Amiel, Jeanne, Martinovic, Jelena, Delanne, Julian, Albuisson, Juliette, Lambert, Laëtitia, Perrin, Laurence, Ousager, Lilian Bomme, Van Maldergem, Lionel, Pinson, Lucile, Ruaud, Lyse, Samimi, Mahtab, Bournez, Marie, Bonnet-Dupeyron, Marie Noëlle, Vincent, Marie, Jacquemont, Marie-Line, Cordier-Alex, Marie-Pierre, Gérard-Blanluet, Marion, Willems, Marjolaine, Spodenkiewicz, Marta, Doco-Fenzy, Martine, Rossi, Massimiliano, Renaud, Mathilde, Fradin, Mélanie, Mathieu, Michèle, Holder-Espinasse, Muriel H., Houcinat, Nada, Hanna, Nadine, Leperrier, Nathalie, Chassaing, Nicolas, Philip, Nicole, Boute, Odile, Van Kien, Philippe Khau, Parent, Philippe, Bitoun, Pierre, Sarda, Pierre, Vabres, Pierre, Jouk, Pierre-Simon, Touraine, Renaud, El Chehadeh, Salima, Whalen, Sandra, Marlin, Sandrine, Passemard, Sandrine, Grotto, Sarah, Bellanger, Séverine Audebert, Blesson, Sophie, Nambot, Sophie, Naudion, Sophie, Lyonnet, Stanislas, Odent, Sylvie, Attie-Bitach, Tania, Busa, Tiffany, Drouin-Garraud, Valérie, Layet, Valérie, Bizaoui, Varoona, Cusin, Véronica, Capri, Yline, Alembik, Yves, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Denommé-Pichon, Anne-Sophie, Matalonga, Leslie, de Boer, Elke, Jackson, Adam, Benetti, Elisa, Banka, Siddharth, Bruel, Ange-Line, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Duffourd, Yannis, Ellwanger, Kornelia, Fallerini, Chiara, Gilissen, Christian, Graessner, Holm, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jean-Marçais, Nolwenn, Kleefstra, Tjitske, López-Martín, Estrella, Macek, Milan, Mencarelli, Maria Antonietta, Moutton, Sébastien, Pfundt, Rolph, Pizzi, Simone, Posada, Manuel, Radio, Francesca Clementina, Renieri, Alessandra, Rooryck, Caroline, Ryba, Lukas, Safraou, Hana, Schwarz, Martin, Tartaglia, Marco, Thauvin-Robinet, Christel, Thevenon, Julien, Tran Mau-Them, Frédéric, Trimouille, Aurélien, Votypka, Pavel, de Vries, Bert B. A., Willemsen, Marjolein H., Zurek, Birte, Verloes, Alain, Philippe, Christophe, Abbott, Kristin M., Faivre, Laurence, Kerstjens, Mieke, Martín, Estrella López, Macek Jr., Milan, Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Pinelli, Michele, Radio, Francesca C., Riess, Olaf, Agathe, Jean-Madeleine De Sainte, Santen, Gijs W. E., Thauvin, Christel, Torella, Annalaura, Vissers, Lisenka, Vitobello, Antonio, Zguro, Kristina, Boer, Elke De, Cohen, Enzo, Danis, Daniel, Gao, Fei, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, te Paske, Iris B. A. W., Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vandrovcova, Jana, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, `t Hoen, Peter A. C., Vissers, Lisenka E. L. M., Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, Paske, Iris Te, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Alexander, Elizabeth, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Ben Yaou, Rabah, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Li\vsková, Petra, Dole\vzalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Efthymiou, Stephanie, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Varavallo, Alessandra, Banfi, Sandro, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Kerstjens Frederikse, Wilhemina S., Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, Lacombe, Didier, Trimouille, Aurelien, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Hackman, Peter, Udd, Bjarne, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Osorio, Andrés Nascimento, Depienne, Christel, Roos, Andreas, Cordts, Isabell, Deschauer, Marcus, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Claeys, Kristl, Boztug, Kaan, Haimel, Matthias, W.E, Gijs, Ruivenkamp, Claudia A. L., Natera de Benito, Daniel, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Balicza, Peter, Molnar, Maria Judit, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Delgado, Beatriz Martínez, Alonso García de la Rosa, F. Javier, Schröck, Evelin, Rump, Andreas, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Chinnery, Patrick F., Ratnaike, Thiloka, Schon, Katherine, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, May, Patrick, Beeson, David, Cossins, Judith, Furini, Simone, Afenjar, Alexandra, Goldenberg, Alice, Masurel, Alice, Phan, Alice, Dieux-Coeslier, Anne, Fargeot, Anne, Guerrot, Anne-Marie, Toutain, Annick, Molin, Arnaud, Sorlin, Arthur, Putoux, Audrey, Jouret, Béatrice, Laudier, Béatrice, Demeer, Bénédicte, Doray, Bérénice, Bonniaud, Bertille, Isidor, Bertrand, Gilbert-Dussardier, Brigitte, Leheup, Bruno, Reversade, Bruno, Paul, Carle, Vincent-Delorme, Catherine, Neiva, Cecilia, Poirsier, Céline, Quélin, Chloé, Chiaverini, Christine, Coubes, Christine, Francannet, Christine, Colson, Cindy, Desplantes, Claire, Wells, Constance, Goizet, Cyril, Sanlaville, Damien, Amram, Daniel, Lehalle, Daphné, Geneviève, David, Gaillard, Dominique, Zivi, Einat, Sarrazin, Elisabeth, Steichen, Elisabeth, Schaefer, Élise, Lacaze, Elodie, Jacquemin, Emmanuel, Bongers, Ernie, Kilic, Esra, Colin, Estelle, Giuliano, Fabienne, Prieur, Fabienne, Laffargue, Fanny, Morice-Picard, Fanny, Petit, Florence, Cartault, François, Feillet, François, Baujat, Geneviève, Morin, Gilles, Diene, Gwenaëlle, Journel, Hubert, Perthus, Isabelle, Lespinasse, James, Alessandri, Jean-Luc, Amiel, Jeanne, Martinovic, Jelena, Delanne, Julian, Albuisson, Juliette, Lambert, Laëtitia, Perrin, Laurence, Ousager, Lilian Bomme, Van Maldergem, Lionel, Pinson, Lucile, Ruaud, Lyse, Samimi, Mahtab, Bournez, Marie, Bonnet-Dupeyron, Marie Noëlle, Vincent, Marie, Jacquemont, Marie-Line, Cordier-Alex, Marie-Pierre, Gérard-Blanluet, Marion, Willems, Marjolaine, Spodenkiewicz, Marta, Doco-Fenzy, Martine, Rossi, Massimiliano, Renaud, Mathilde, Fradin, Mélanie, Mathieu, Michèle, Holder-Espinasse, Muriel H., Houcinat, Nada, Hanna, Nadine, Leperrier, Nathalie, Chassaing, Nicolas, Philip, Nicole, Boute, Odile, Van Kien, Philippe Khau, Parent, Philippe, Bitoun, Pierre, Sarda, Pierre, Vabres, Pierre, Jouk, Pierre-Simon, Touraine, Renaud, El Chehadeh, Salima, Whalen, Sandra, Marlin, Sandrine, Passemard, Sandrine, Grotto, Sarah, Bellanger, Séverine Audebert, Blesson, Sophie, Nambot, Sophie, Naudion, Sophie, Lyonnet, Stanislas, Odent, Sylvie, Attie-Bitach, Tania, Busa, Tiffany, Drouin-Garraud, Valérie, Layet, Valérie, Bizaoui, Varoona, Cusin, Véronica, Capri, Yline, and Alembik, Yves

Abstract

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock.

Published
2023

19. Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Yaldiz, Burcu, Kucuk, Erdi, Hampstead, Juliet, Hofste, Tom, Pfundt, Rolph, Corominas Galbany, Jordi, Rinne, Tuula, Yntema, Helger G., Hoischen, Alexander, Nelen, Marcel, Gilissen, Christian, consortium, Solve-R. D., Riess, Olaf, Haack, Tobias B., Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoen, Peter A. C. T, Vissers, Lisenka E. L. M., Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, te Paske, Iris, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Matalonga, Leslie, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Efthymiou, Stephanie, Morsy, Heba, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Abbott, Kristin M., Frederikse, Wilhemina Skerstjens, Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, de Sainte Agathe, Jean-Madeleine, Rooryck, Caroline, Lacombe, Didier, Trimouille, Aurelien, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Balicza, Peter, Molnar, Maria Judit, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Osorio, Andrés Nascimento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Beeson, David, Cossins, Judith, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Horvath, Rita, Chinnery, Patrick F., Ratnaike, Thiloka, Gao, Fei, Schon, Katherine, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Başak, Ayşe Nazlı, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Claeys, Kristl, Santen, Gijs W. E., Bijlsma, Emilia K., Hoffer, Mariette J. V., Ruivenkamp, Claudia A. L., Boztug, Kaan, Haimel, Matthias, Maystadt, Isabelle, Cordts, Isabelle, Deschauer, Marcus, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Depienne, Christel, Roos, Andreas, May, Patrick, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Yaldiz, Burcu, Kucuk, Erdi, Hampstead, Juliet, Hofste, Tom, Pfundt, Rolph, Corominas Galbany, Jordi, Rinne, Tuula, Yntema, Helger G., Hoischen, Alexander, Nelen, Marcel, Gilissen, Christian, consortium, Solve-R. D., Riess, Olaf, Haack, Tobias B., Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoen, Peter A. C. T, Vissers, Lisenka E. L. M., Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, te Paske, Iris, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Matalonga, Leslie, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Efthymiou, Stephanie, Morsy, Heba, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Abbott, Kristin M., Frederikse, Wilhemina Skerstjens, Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, de Sainte Agathe, Jean-Madeleine, Rooryck, Caroline, Lacombe, Didier, Trimouille, Aurelien, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Balicza, Peter, Molnar, Maria Judit, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Osorio, Andrés Nascimento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Beeson, David, Cossins, Judith, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Horvath, Rita, Chinnery, Patrick F., Ratnaike, Thiloka, Gao, Fei, Schon, Katherine, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Başak, Ayşe Nazlı, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Claeys, Kristl, Santen, Gijs W. E., Bijlsma, Emilia K., Hoffer, Mariette J. V., Ruivenkamp, Claudia A. L., Boztug, Kaan, Haimel, Matthias, Maystadt, Isabelle, Cordts, Isabelle, Deschauer, Marcus, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Depienne, Christel, Roos, Andreas, and May, Patrick

Abstract

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques.

Published
2023

20. Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series

Author

Tack, L.J.W., Brachet, Cécile, Beauloye, Véronique, Heinrichs, Claudine, Boros, EMESE, De Waele, Kathleen, Van Der Straaten, Saskia, Van Aken, Sara, Craen, Margarita, Lemay, A., Rochtus, Anne, casteels, Kristina, Beckers, Dominique, Mouraux, Thierry, Logghe, Karel, Van Loocke, Marlies, Massa, Guy, Van de Vijver, Koen, Syryn, Hannes, Van De Velde, Julie, De Baere, Elfride, Verdin, Hannah, Cools, Martine B C M M., Tack, L.J.W., Brachet, Cécile, Beauloye, Véronique, Heinrichs, Claudine, Boros, EMESE, De Waele, Kathleen, Van Der Straaten, Saskia, Van Aken, Sara, Craen, Margarita, Lemay, A., Rochtus, Anne, casteels, Kristina, Beckers, Dominique, Mouraux, Thierry, Logghe, Karel, Van Loocke, Marlies, Massa, Guy, Van de Vijver, Koen, Syryn, Hannes, Van De Velde, Julie, De Baere, Elfride, Verdin, Hannah, and Cools, Martine B C M M.

Abstract

STUDY QUESTION: What is the long-term outcome of individuals born with bilateral testicular regression (BTR) in relation to its underlying etiology? SUMMARY ANSWER: Statural growth and pubertal development are adequate with incremental doses of testosterone replacement therapy (TRT); however, penile growth is often suboptimal, especially in those with a suspected genetic etiology (i.e. heterozygous DHX37 variants) or a micropenis at birth. WHAT IS KNOWN ALREADY: BTR is a rare and poorly understood condition. Although a vascular origin has been postulated, heterozygous missense variants in DHX37 have been attributed to the phenotype as well. How these various etiologies impact the clinical phenotype, gonadal histology and outcome of BTR remains unclear. STUDY DESIGN, SIZE, DURATION: For this cross-sectional study, individuals with BTR were recruited in eight Belgian pediatric endocrinology departments, between December 2019 and December 2022. A physical exam was performed cross-sectionally in all 17 end-pubertal participants and a quality of care questionnaire was completed by 11 of them. Exome-based panel testing of 241 genes involved in gonadal development and spermatogenesis was performed along with a retrospective analysis of presentation and management. A centralized histological review of gonadal rests was done for 10 participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 35 participants (33 with male, 1 with female, and 1 with non-binary gender identity) were recruited at a mean age of 15.0 ± 5.7 years. MAIN RESULTS AND THE ROLE OF CHANCE: The median age at presentation was 1.2 years [0-14 years]. Maternal gestational complications were common (38.2%), with a notably high incidence of monozygotic twin pregnancies (8.8%). Heterozygous (likely) pathogenic missense variants in DHX37 (p.Arg334Trp and p.Arg308Gln) were found in three participants. No other (likely) pathogenic variants were found. All three participants with a DHX37 variant had a microph, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2023

21. Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Author

Yaldiz, Burcu, Kucuk, Erdi, Hampstead, Juliet, Hofste, Tom, Pfundt, Rolph, Corominas Galbany, Jordi, Rinne, Tuula, Yntema, Helger G., Hoischen, Alexander, Nelen, Marcel, Gilissen, Christian, consortium, Solve-R. D., Riess, Olaf, Haack, Tobias B., Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoen, Peter A. C. T, Vissers, Lisenka E. L. M., Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, te Paske, Iris, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Matalonga, Leslie, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Efthymiou, Stephanie, Morsy, Heba, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Abbott, Kristin M., Frederikse, Wilhemina Skerstjens, Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, de Sainte Agathe, Jean-Madeleine, Rooryck, Caroline, Lacombe, Didier, Trimouille, Aurelien, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Balicza, Peter, Molnar, Maria Judit, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Osorio, Andrés Nascimento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Beeson, David, Cossins, Judith, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Horvath, Rita, Chinnery, Patrick F., Ratnaike, Thiloka, Gao, Fei, Schon, Katherine, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Başak, Ayşe Nazlı, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Claeys, Kristl, Santen, Gijs W. E., Bijlsma, Emilia K., Hoffer, Mariette J. V., Ruivenkamp, Claudia A. L., Boztug, Kaan, Haimel, Matthias, Maystadt, Isabelle, Cordts, Isabelle, Deschauer, Marcus, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Depienne, Christel, Roos, Andreas, May, Patrick, and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Multidisciplinary, general & others [D99] [Human health sciences]
Abstract

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques.

Published
2023

22. The Role of MCM9 in the Etiology of Sertoli Cell-Only Syndrome and Premature Ovarian Insufficiency

Author

Potorac, Iulia, primary, Laterre, Marie, additional, Malaise, Olivier, additional, Nechifor, Vlad, additional, Fasquelle, Corinne, additional, Colleye, Orphal, additional, Detrembleur, Nancy, additional, Verdin, Hannah, additional, Symoens, Sofie, additional, De Baere, Elfride, additional, Daly, Adrian F., additional, Bours, Vincent, additional, Pétrossians, Patrick, additional, and Pintiaux, Axelle, additional

Published
2023
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23. Exome sequencing and multigene panel testing in 1,411 patients with adult-onset neurologic disorders

Author

Schuermans, Nika, Verdin, Hannah, Ghijsels, Jody, Hellemans, Madeleine, Debackere, Elke, Bogaert, Elke, Symoens, Sofie, Naesens, Leslie, Lecomte, Elien, Crosiers, David, Bergmans, Bruno, Verhoeven, Kristof, Poppe, Bruce, Laureys, Guy, Herdewyn, Sarah, Van Langenhove, Tim, Santens, Patrick, De Bleecker, Jan, Hemelsoet, Dimitri, Dermaut, Bart, and for Program for Undiagnosed Rare Diseases (UD-PrOZA), [missing]

Subjects
Medicine and Health Sciences, Neurology (clinical), Genetics (clinical)
Published
2023

24. Endocrine outcome and seminal parameters in young adult men born with hypospadias: A cross-sectional cohort study

Author

Tack, Lloyd J.W., primary, Spinoit, Anne-Françoise, additional, Hoebeke, Piet, additional, Riedl, Stefan, additional, Springer, Alexander, additional, Tonnhofer, Ursula, additional, Hiess, Manuela, additional, Weninger, Julia, additional, Mahmoud, Ahmed, additional, Tilleman, Kelly, additional, Van Laecke, Erik, additional, Juul, Anders, additional, Albrethsen, Jakob, additional, De Baere, Elfride, additional, Van De Velde, Julie, additional, Verdin, Hannah, additional, and Cools, Martine, additional

Published
2022
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25. Endocrine outcome and seminal parameters in young adult men born with hypospadias:A cross-sectional cohort study

Author

Tack, Lloyd J. W., Spinoit, Anne Françoise, Hoebeke, Piet, Riedl, Stefan, Springer, Alexander, Tonnhofer, Ursula, Hiess, Manuela, Weninger, Julia, Mahmoud, Ahmed, Tilleman, Kelly, Van Laecke, Erik, Juul, Anders, Albrethsen, Jakob, De Baere, Elfride, Van De Velde, Julie, Verdin, Hannah, Cools, Martine, Tack, Lloyd J. W., Spinoit, Anne Françoise, Hoebeke, Piet, Riedl, Stefan, Springer, Alexander, Tonnhofer, Ursula, Hiess, Manuela, Weninger, Julia, Mahmoud, Ahmed, Tilleman, Kelly, Van Laecke, Erik, Juul, Anders, Albrethsen, Jakob, De Baere, Elfride, Van De Velde, Julie, Verdin, Hannah, and Cools, Martine

Abstract

Background: Hypospadias affects around 1/200 newborn males. Intrauterine testicular dysfunction may underlie a subset of cases. The long-term endocrine and reproductive outcomes in these men remain largely unknown. Methods: Cross-sectional study in Ghent and Vienna University Hospitals to assess the endocrine and seminal parameters of young adult men (16–21 years) born with non-syndromic hypospadias (NSH) (n = 193) compared to healthy typical males (n = 50). Assessments included physical exam, semen analysis, hormone assays and exome-based gene panel analysis (474 genes). Findings: All participants had experienced a spontaneous puberty, in spite of higher LH and INSL3 levels than typical males. Oligo- or azoospermia was observed in 32/172 (18·6%; 99%-CI: 12·2–27·4%) of NSH men; but in 5/16 (31·3%; 99%-CI: 11·1;62·4%) of complex NSH men and in 13/22 (59·1%; 99%-CI: 33·2–80·7%) of those born small for gestational age (SGA). No (likely) pathogenic coding variants were found in the investigated genes. Suboptimal statural growth affected 8/23 (34·8%; 99%-CI: 15·4–61·0%) of men born SGA with NSH. Interpretation: Spermatogenesis is significantly compromised in NSH men, especially in those born SGA or those with complex NSH. Long-term andrological follow-up is recommended, including end-pubertal semen analysis. No clear monogenic causes could be demonstrated in our cohort even in proximal or complex NSH. Being born SGA with NSH is frequently associated with poor catch-up growth, requiring growth hormone therapy in some. Funding: Research grants from the European Society of Paediatric Endocrinology, the Belgian Society of Pediatrics, the Belgian Society of Pediatric Endocrinology and Diabetology and the Research Foundation Flanders (FWO).

Published
2022

26. Correction: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease

Author

Van de Sompele, Stijn, Smith, Claire, Karali, Marianthi, Corton, Marta, Van Schil, Kristof, Peelman, Frank, Cherry, Timothy, Rosseel, Toon, Verdin, Hannah, Derolez, Julien, Van Laethem, Thalia, Khan, Kamron N., McKibbin, Martin, Toomes, Carmel, Ali, Manir, Torella, Annalaura, Testa, Francesco, Jimenez, Belen, Simonelli, Francesca, De Zaeytijd, Julie, Van den Ende, Jenneke, Leroy, Bart P., Coppieters, Frauke, Ayuso, Carmen, Inglehearn, Chris F., Banfi, Sandro, and De Baere, Elfride

Published
2019
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27. Additional file 2 of Shortcutting the diagnostic odyssey: the multidisciplinary Program for Undiagnosed Rare Diseases in adults (UD-PrOZA)

Author

Schuermans, Nika, Hemelsoet, Dimitri, Terryn, Wim, Steyaert, Sanne, Van Coster, Rudy, Coucke, Paul J., Steyaert, Wouter, Callewaert, Bert, Bogaert, Elke, Verloo, Patrick, Vanlander, Arnaud V., Debackere, Elke, Ghijsels, Jody, LeBlanc, Pontus, Verdin, Hannah, Naesens, Leslie, Haerynck, Filomeen, Callens, Steven, Dermaut, Bart, and Poppe, Bruce

Abstract

Additional file 2. An overview of all genetic diagnoses is provided (Table S3).

Published
2022
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28. Additional file 1 of Shortcutting the diagnostic odyssey: the multidisciplinary Program for Undiagnosed Rare Diseases in adults (UD-PrOZA)

Author

Schuermans, Nika, Hemelsoet, Dimitri, Terryn, Wim, Steyaert, Sanne, Van Coster, Rudy, Coucke, Paul J., Steyaert, Wouter, Callewaert, Bert, Bogaert, Elke, Verloo, Patrick, Vanlander, Arnaud V., Debackere, Elke, Ghijsels, Jody, LeBlanc, Pontus, Verdin, Hannah, Naesens, Leslie, Haerynck, Filomeen, Callens, Steven, Dermaut, Bart, and Poppe, Bruce

Abstract

Additional file 1. Supplementary methods, figures and tables (Figures S1, S2, S3 and Tables S1, S2).

Published
2022
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31. Expanding the clinical spectrum and management of traboulsi syndrome: report on two siblings homozygous for a novel pathogenic variant in ASPH

Author

Van Hoorde, Tom, Nerinckx, Fanny, Kreps, Elke, Roels, Dimitri, Huyghe, Philippe, Van Heetvelde, Mattias, Verdin, Hannah, De Baere, Elfride, Balikova, Irina, and Leroy, Bart P.

Subjects
genetic structures, sense organs, eye diseases
Abstract

Background: Traboulsi syndrome is a very rare, syndromic form of ectopia lentis that is potentially sight-threatening at a young age. It is characterized by typical facial, skeletal and ocular signs. Materials and Methods: Two siblings, born to consanguineous parents, with a clinical phenotype consistent with Traboulsi syndrome, underwent extensive ophthalmic imaging and exome-based genetic testing. Both were treated with unilateral clear lens extraction via a limbal approach. Results: Two siblings, one male and one female, presented with systemic and ocular features consistent with Traboulsi syndrome. Lens subluxation was present in all 4fouraffected eyes, and spontaneous subconjunctival bleb formation was detected in one eye. This eye also showed evidence of keratoconus-related corneal thinning. The clinical diagnosis of Traboulsi syndrome was confirmed molecularly. A homozygous, novel, pathogenic nonsense variant was identified in exon 25 of the ASPH gene: c.2181_2183dup, p.(Val727_Trp728insTer). Excellent visual outcomes following clear lens extraction and postoperative rigid gas-permeable contact lens fitting were obtained. Conclusions: We expanded the genetic spectrum of Traboulsi syndrome with a novel frameshift variant in the ASPH gene. We showed that lensectomy followed by gas-permeable contact lenses is an efficient therapeutic approach to treat lens subluxation in Traboulsi syndrome. However, lifelong follow-up is crucial to avoid (late) postoperative complications.

Published
2021
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32. Correction: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease (Genetics in Medicine, (2018), 10.1038/s41436-018-0345-5)

Author

Van de Sompele, Stijn, Smith, Claire, Karali, Marianthi, Corton, Marta, Van Schil, Kristof, Peelman, Frank, Cherry, Timothy, Rosseel, Toon, Verdin, Hannah, Derolez, Julien, Van Laethem, Thalia, Khan, Kamron N., McKibbin, Martin, Toomes, Carmel, Ali, Manir, Torella, Annalaura, Testa, Francesco, Jimenez, Belen, Simonelli, Francesca, De Zaeytijd, Julie, Van den Ende, Jenneke, Leroy, Bart P., Coppieters, Frauke, Ayuso, Carmen, Inglehearn, Chris F., Banfi, Sandro, De Baere, Elfride, Van de Sompele, Stijn, Smith, Claire, Karali, Marianthi, Corton, Marta, Van Schil, Kristof, Peelman, Frank, Cherry, Timothy, Rosseel, Toon, Verdin, Hannah, Derolez, Julien, Van Laethem, Thalia, Khan, Kamron N., Mckibbin, Martin, Toomes, Carmel, Ali, Manir, Torella, Annalaura, Testa, Francesco, Jimenez, Belen, Simonelli, Francesca, De Zaeytijd, Julie, Van den Ende, Jenneke, Leroy, Bart P., Coppieters, Frauke, Ayuso, Carmen, Inglehearn, Chris F., Banfi, Sandro, and De Baere, Elfride

Abstract

The original version of this Article contained an incorrect version of Fig.3, which included two variants initially shown in black text in Fig. 3a that the authors removed from the final manuscript. The correct version of Fig. 3 without the two variants now appears in the PDF and HTML versions of the Article.

Published
2019

34. Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

Author

Yan, Kezhi, primary, Rousseau, Justine, additional, Machol, Keren, additional, Cross, Laura A., additional, Agre, Katherine E., additional, Gibson, Cynthia Forster, additional, Goverde, Anne, additional, Engleman, Kendra L., additional, Verdin, Hannah, additional, De Baere, Elfride, additional, Potocki, Lorraine, additional, Zhou, Dihong, additional, Cadieux-Dion, Maxime, additional, Bellus, Gary A., additional, Wagner, Monisa D., additional, Hale, Rebecca J., additional, Esber, Natacha, additional, Riley, Alan F., additional, Solomon, Benjamin D., additional, Cho, Megan T., additional, McWalter, Kirsty, additional, Eyal, Roy, additional, Hainlen, Meagan K., additional, Mendelsohn, Bryce A., additional, Porter, Hillary M., additional, Lanpher, Brendan C., additional, Lewis, Andrea M., additional, Savatt, Juliann, additional, Thiffault, Isabelle, additional, Callewaert, Bert, additional, Campeau, Philippe M., additional, and Yang, Xiang-Jiao, additional

Published
2020
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35. Correction: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations

Author

Van Schil, Kristof, primary, Naessens, Sarah, additional, Van de Sompele, Stijn, additional, Carron, Marjolein, additional, Aslanidis, Alexander, additional, Van Cauwenbergh, Caroline, additional, Mayer, Anja K., additional, Van Heetvelde, Mattias, additional, Bauwens, Miriam, additional, Verdin, Hannah, additional, Coppieters, Frauke, additional, Greenberg, Michael E., additional, Yang, Marty G., additional, Karlstetter, Marcus, additional, Langmann, Thomas, additional, De Preter, Katleen, additional, Kohl, Susanne, additional, Cherry, Timothy J., additional, Leroy, Bart P., additional, De Baere, Elfride, additional, Lupski, James R, additional, Carvalho, Claudia, additional, van Min, Max, additional, Klous, Petra, additional, De Jaegere, Sarah, additional, and Hooghe, Sally, additional

Published
2019
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36. Avarietyofalu-mediated copy number variations can underlie il-12rβ1 deficiency

Author

Rosain, Jérémie, Oleaga-Quintas, Carmen, Deswarte, Caroline, Verdin, Hannah, Marot, Stéphane, Syridou, Garyfallia, Mansouri, Mahboubeh, Mahdaviani, Seyed Alireza, Venegas-Montoya, Edna, Tsolia, Maria, Mesdaghi, Mehrnaz, Chernyshova, Liudmyla, Stepanovskiy, Yuriy, Parvaneh, Nima, Mansouri, Davood, Pedraza-Sánchez, Sigifredo, Bondarenko, Anastasia, Espinosa-Padilla, Sara Elva, Yamazaki-Nakashimada, Marco Antonio, Nieto-Patlán, Alejandro, Kerner, Gaspard, Lambert, Nathalie, Jacques, Corinne, Corvilain, Emilie, Migaud, Mélanie, Grandin, Virginie, Herrera, María Teresa, Jabot-Hanin, Fabienne, Boisson-Dupuis, Stéphanie, Picard, Capucine, Nitschké, Patrick, Puel, Anne, Tores, Frederic, Abel, Laurent, Blancas-Galicia, Lizbeth, De Baere, Elfride, Bole-Feysot, Christine, Casanova, Jean-Laurent, Bustamante, Jacinta, Rosain, Jérémie, Oleaga-Quintas, Carmen, Deswarte, Caroline, Verdin, Hannah, Marot, Stéphane, Syridou, Garyfallia, Mansouri, Mahboubeh, Mahdaviani, Seyed Alireza, Venegas-Montoya, Edna, Tsolia, Maria, Mesdaghi, Mehrnaz, Chernyshova, Liudmyla, Stepanovskiy, Yuriy, Parvaneh, Nima, Mansouri, Davood, Pedraza-Sánchez, Sigifredo, Bondarenko, Anastasia, Espinosa-Padilla, Sara Elva, Yamazaki-Nakashimada, Marco Antonio, Nieto-Patlán, Alejandro, Kerner, Gaspard, Lambert, Nathalie, Jacques, Corinne, Corvilain, Emilie, Migaud, Mélanie, Grandin, Virginie, Herrera, María Teresa, Jabot-Hanin, Fabienne, Boisson-Dupuis, Stéphanie, Picard, Capucine, Nitschké, Patrick, Puel, Anne, Tores, Frederic, Abel, Laurent, Blancas-Galicia, Lizbeth, De Baere, Elfride, Bole-Feysot, Christine, Casanova, Jean-Laurent, and Bustamante, Jacinta

Abstract

Purpose Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs. Methods We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS). Results We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n =1)orintrans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). Conclusion The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

37. Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations

Author

Van Schil, Kristof, Naessens, Sarah, Van de Sompele, Stijn, Carron, Marjolein, Aslanidis, Alexander, Van Cauwenbergh, Caroline, Mayer, Anja Kathrin, Van Heetvelde, Mattias, Bauwens, Miriam, Verdin, Hannah, Coppieters, Frauke, Greenberg, Michael E., Yang, Marty G., Karlstetter, Marcus, Langmann, Thomas, De Preter, Katleen, Kohl, Susanne, Cherry, Timothy J., Leroy, Bart P., De Baere, Elfride, Van Schil, Kristof, Naessens, Sarah, Van de Sompele, Stijn, Carron, Marjolein, Aslanidis, Alexander, Van Cauwenbergh, Caroline, Mayer, Anja Kathrin, Van Heetvelde, Mattias, Bauwens, Miriam, Verdin, Hannah, Coppieters, Frauke, Greenberg, Michael E., Yang, Marty G., Karlstetter, Marcus, Langmann, Thomas, De Preter, Katleen, Kohl, Susanne, Cherry, Timothy J., Leroy, Bart P., and De Baere, Elfride

Abstract

Purpose: Part of the hidden genetic variation in heterogeneous genetic conditions such as inherited retinal diseases (IRDs) can be explained by copy-number variations (CNVs). Here, we explored the genomic landscape of IRD genes listed in RetNet to identify and prioritize those genes susceptible to CNV formation. Methods: RetNet genes underwent an assessment of genomic features and of CNV occurrence in the Database of Genomic Variants and literature. CNVs identified in an IRD cohort were characterized using targeted locus amplification (TLA) on extracted genomic DNA. Results: Exhaustive literature mining revealed 1,345 reported CNVs in 81 different IRD genes. Correlation analysis between rankings of genomic features and CNV occurrence demonstrated the strongest correlation between gene size and CNV occurrence of IRD genes. Moreover, we identified and delineated 30 new CNVs in IRD cases, 13 of which are novel and three of which affect noncoding, putative cis-regulatory regions. Finally, the breakpoints of six complex CNVs were determined using TLA in a hypothesis-neutral manner. Conclusion: We propose a ranking of CNV-prone IRD genes and demonstrate the efficacy of TLA for the characterization of CNVs on extracted DNA. Finally, this IRD-oriented CNV study can serve as a paradigm for other genetically heterogeneous Mendelian diseases with hidden genetic variation.

Published
2018

38. Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Author

Pathologie Pathologen staf, Baetens, Dorien, Güran, Tülay, Mendonca, Berenice B., Gomes, Nathalia L., De Cauwer, Lode, Peelman, Frank, Verdin, Hannah, Vuylsteke, Marnik, Van Der Linden, Malaïka, Atay, Zeynep, Bereket, Abdullah, De Krijger, Ronald R., De Preter, Katleen, Domenice, Sorahia, Turan, Serap, Stoop, Hans, Looijenga, Leendert H., De Bosscher, Karolien, Cools, Martine, De Baere, Elfride, ESR2 Study Group, Pathologie Pathologen staf, Baetens, Dorien, Güran, Tülay, Mendonca, Berenice B., Gomes, Nathalia L., De Cauwer, Lode, Peelman, Frank, Verdin, Hannah, Vuylsteke, Marnik, Van Der Linden, Malaïka, Atay, Zeynep, Bereket, Abdullah, De Krijger, Ronald R., De Preter, Katleen, Domenice, Sorahia, Turan, Serap, Stoop, Hans, Looijenga, Leendert H., De Bosscher, Karolien, Cools, Martine, De Baere, Elfride, and ESR2 Study Group

Published
2018

39. Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations

Author

Van Schil, Kristof, primary, Naessens, Sarah, additional, Van de Sompele, Stijn, additional, Carron, Marjolein, additional, Aslanidis, Alexander, additional, Van Cauwenbergh, Caroline, additional, Mayer, Anja K., additional, Van Heetvelde, Mattias, additional, Bauwens, Miriam, additional, Verdin, Hannah, additional, Coppieters, Frauke, additional, Greenberg, Michael E., additional, Yang, Marty G., additional, Karlstetter, Marcus, additional, Langmann, Thomas, additional, De Preter, Katleen, additional, Kohl, Susanne, additional, Cherry, Timothy J., additional, Leroy, Bart P., additional, Lupski, James R., additional, Carvalho, Claudia, additional, van Min, Max, additional, Klous, Petra, additional, De Jaegere, Sarah, additional, Hooghe, Sally, additional, and De Baere, Elfride, additional

Published
2018
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40. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

Author

McEntagart, Meriel, Williamson, Kathleen A, Rainger, Jacqueline K, Wheeler, Ann, Seawright, Anne, De Baere, Elfride, Verdin, Hannah, Bergendahl, L Therese, Quigley, Alan, Rainger, Joe, Dixit, Abhijit, Sarkar, Ajoy, López Laso, Eduardo, Sanchez-Carpintero, Rocio, Barrio, Jesus, Bitoun, Pierre, Prescott, Trine, Riise, Ruth, McKee, Shane, Cook, Jackie, McKie, Lisa, Ceulemans, Berten, Meire, Françoise, Temple, I Karen, Prieur, Fabienne, Williams, Jonathan, Clouston, Penny, Németh, Andrea H, Banka, Siddharth, Bengani, Hemant, Handley, Mark, Freyer, Elisabeth, Ross, Allyson, DDD Study, van Heyningen, Veronica, Marsh, Joseph A, Elmslie, Frances, and FitzPatrick, David R

Subjects
Adult, Male, cerebellar hypoplasia, inositol triphosphate, Adolescent, Cerebellar Ataxia, Protein Conformation, aniridia, Mice, Intellectual Disability, cerebellar vermis, Animals, Humans, Inositol 1,4,5-Trisphosphate Receptors, Lymphocytes, Child, Cells, Cultured, iris, Genes, Dominant, ITPR1, calcium, Microscopy, Confocal, Middle Aged, Pedigree, Mutation, Female, ACTA2
Abstract

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions.

Published
2016

42. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

Author

McEntagart, Meriel, primary, Williamson, Kathleen A., additional, Rainger, Jacqueline K., additional, Wheeler, Ann, additional, Seawright, Anne, additional, De Baere, Elfride, additional, Verdin, Hannah, additional, Bergendahl, L. Therese, additional, Quigley, Alan, additional, Rainger, Joe, additional, Dixit, Abhijit, additional, Sarkar, Ajoy, additional, López Laso, Eduardo, additional, Sanchez-Carpintero, Rocio, additional, Barrio, Jesus, additional, Bitoun, Pierre, additional, Prescott, Trine, additional, Riise, Ruth, additional, McKee, Shane, additional, Cook, Jackie, additional, McKie, Lisa, additional, Ceulemans, Berten, additional, Meire, Françoise, additional, Temple, I. Karen, additional, Prieur, Fabienne, additional, Williams, Jonathan, additional, Clouston, Penny, additional, Németh, Andrea H., additional, Banka, Siddharth, additional, Bengani, Hemant, additional, Handley, Mark, additional, Freyer, Elisabeth, additional, Ross, Allyson, additional, van Heyningen, Veronica, additional, Marsh, Joseph A., additional, Elmslie, Frances, additional, and FitzPatrick, David R., additional

Published
2016
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43. Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

Author

Van Schil, Kristof, Meire, Francoise, Karlstetter, Marcus, Bauwens, Miriam, Verdin, Hannah, Coppieters, Frauke, Scheiffert, Eva, Van Nechel, Christian, Langmann, Thomas, Deconinck, Nicolas, De Baere, Elfride, Van Schil, Kristof, Meire, Francoise, Karlstetter, Marcus, Bauwens, Miriam, Verdin, Hannah, Coppieters, Frauke, Scheiffert, Eva, Van Nechel, Christian, Langmann, Thomas, Deconinck, Nicolas, and De Baere, Elfride

Abstract

Purpose: The aim of this study was to identify the genetic cause of early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy in a consanguineous family. Methods: An affected 6-month-old child underwent neurological and ophthalmological examinations. Genetic analyses included homozygosity mapping, copy number analysis, conventional polymerase chain reaction, Sanger sequencing, quantitative polymerase chain reaction, and whole-exome sequencing. Expression analysis of GRID2 was performed by quantitative polymerase chain reaction and immunohistochemistry. Results: A homozygous deletion of exon 2 of GRID2 (p.G1y30_Glu-81del) was identified in the proband. GRID2 encodes an ionotropic glutamate receptor known to be selectively expressed in cerebellar Purkinje cells. Here, we demonstrated GRID2 expression in human adult retina and retinal pigment epithelium. In addition, Grid2 expression was demonstrated in different stages of murine retinal development. GRID2 immunostaining was shown in murine and human retina. Whole-exome sequencing in the proband did not provide arguments for other disease-causing mutations, supporting the idea that the phenotype observed represents a single clinical entity. Conclusion: We identified GRID2 as an underlying disease gene of early-onset autosomal recessive cerebellar ataxia with retinal dystrophy, expanding the clinical spectrum of GRID2 deletion mutants. We demonstrated for the first time GRID2 expression and localization in human and murine retina, providing evidence for a novel functional role of GRID2 in the retina. Genet Med advance online publication 14 August 2014

Published
2015

44. Novel FRMD7 mutations and genomic rearrangement expand the molecular pathogenesis of X-linked idiopathic infantile nystagmus

Author

Almoallem, Basamat, Bauwens, Miriam, Janssens, Sandra, Van Cauwenbergh, Caroline, Verdin, Hannah, Hooghe, Sally, Thakur, Prasoon Kumar, Coppieters, Frauke, Leeneer, Kim De, Leroy, Bart B.P., De Baere, Elfride, Walraedt, Sophie, Delbeke, Patricia, De Zaeytijd, Julie, Kestelyn, Philippe, Meire, Françoise, Devriendt, Koenraad, Almoallem, Basamat, Bauwens, Miriam, Janssens, Sandra, Van Cauwenbergh, Caroline, Verdin, Hannah, Hooghe, Sally, Thakur, Prasoon Kumar, Coppieters, Frauke, Leeneer, Kim De, Leroy, Bart B.P., De Baere, Elfride, Walraedt, Sophie, Delbeke, Patricia, De Zaeytijd, Julie, Kestelyn, Philippe, Meire, Françoise, and Devriendt, Koenraad

Abstract

PURPOSE:Idiopathic infantile nystagmus (IIN; OMIM 31700) with X-linked inheritance is one of the most common forms of infantile nystagmus. Up to date, three X-linked loci have been identified, Xp11.4-p11.3 (calcium/calmodulin-dependent serine protein kinase [CASK]), Xp22(GPR143), and Xq26-q27 (FRMD7), respectively. Here, we investigated the role of mutations and copy number variations (CNV) of FRMD7 and GPR143 in the molecular pathogenesis of IIN in 49 unrelated Belgian probands.METHODS. We set up a comprehensive molecular genetic workflow based on Sanger sequencing, targeted next generation sequencing (NGS) and CNV analysis using multiplex ligation–dependent probe amplification (MLPA) for FRMD7 (NM_194277.2) and GPR143(NM_000273.2).RESULTS. In 11/49 probands, nine unique FRMD7 changes were found, five of which are novel:frameshift mutation c.2036del, missense mutations c.801C>A and c.875T>C, splice-site mutation c.497þ5G>A, and one genomic rearrangement (1.29 Mb deletion) in a syndromic case. Additionally, four known mutations were found: c.70G>A, c.886G>C, c.910C>T, and c.660del. The latter was found in three independent families. In silico predictions and segregation testing of the novel mutations support their pathogenic effect. No GPR143 mutations or CNVs were found in the remainder of the probands (38/49).CONCLUSIONS. Overall, genetic defects of FRMD7 were found in 11/49 (22.4%) probands,including the first reported genomic rearrangement of FRMD7 in IIN, expanding its mutational spectrum. Finally, we generate a discovery cohort of IIN patients potentially harboring either hidden a variation of FRMD7 or mutations in genes at known or novel locisustaining the genetic heterogeneity of IIN., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2015

45. Missense mutation outside the forkhead domain of FOXL2 causes a severe form of BPES type II

Author

Haghighi, Alireza, Verdin, Hannah, Haghighi-Kakhki, Hamidreza, Piri, Niloofar, Gohari, Nasrollah Saleh, and De Baere, Elfride

Subjects
Forkhead Box Protein L2, Male, Heterozygote, Genotype, Genetic Linkage, PTOSIS, DNA Mutational Analysis, Molecular Sequence Data, GENOTYPE-PHENOTYPE CORRELATION, Mutation, Missense, Blepharophimosis, Iran, Severity of Illness Index, DISEASE, BLEPHAROPHIMOSIS, Humans, Genes, Dominant, TRANSCRIPTION FACTOR FOXL2, Base Sequence, Biology and Life Sciences, TIME QUANTITATIVE PCR, Forkhead Transcription Factors, TRANSACTIVATION, Pedigree, Protein Structure, Tertiary, Phenotype, EPICANTHUS INVERSUS SYNDROME, Skin Abnormalities, Female, Research Article
Abstract

Purpose: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a developmental disease characterized by a complex eyelid malformation associated or not with premature ovarian failure (POF). BPES is essentially an autosomal dominant disease, due to mutations in the forkhead box L2 (FOXL2) gene, encoding a forkhead transcription factor. More than one hundred unique FOXL2 mutations have been described in BPES in different populations, many of which are missense mutations in the forkhead domain. Here, we report on a very severe form of BPES resulting from a missense mutation outside the forkhead domain. Methods: A clinical and molecular genetic investigation was performed in affected and unaffected members of an Iranian family with BPES. The FOXL2 coding region was sequenced in an index case. Targeted mutation testing was performed in 8 family members. Results: We have identified a heterozygous FOXL2 missense mutation c.650C -> G (p.Ser217Cys) co-segregating with disease in members of a three-generation family with BPES type II. Only few missense mutations have been reported outside the forkhead domain so far. They were all found in mild BPES, in line with in vitro studies demonstrating mostly normal localization and normal or increased transactivation properties of the mutant proteins. Unlike previous studies, affected members of the family studied here showed a severe BPES phenotype, with bilateral amblyopia due to uncorrected ptosis. Conclusions: This is the first study demonstrating a severe BPES phenotype resulting from a FOXL2 missense mutation outside the forkhead domain, expanding our knowledge about the phenotypic consequences of missense mutations outside the forkhead domain in BPES.

Published
2012

46. Profiling of conserved non-coding elements upstream of SHOX and functional characterisation of the SHOX cis-regulatory landscape

Author

Verdin, Hannah, primary, Fernández-Miñán, Ana, additional, Benito-Sanz, Sara, additional, Janssens, Sandra, additional, Callewaert, Bert, additional, De Waele, Kathleen, additional, De Schepper, Jean, additional, François, Inge, additional, Menten, Björn, additional, Heath, Karen E., additional, Gómez-Skarmeta, José Luis, additional, and De Baere, Elfride, additional

Published
2015
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47. Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

Author

Van Schil, Kristof, primary, Meire, Françoise, additional, Karlstetter, Marcus, additional, Bauwens, Miriam, additional, Verdin, Hannah, additional, Coppieters, Frauke, additional, Scheiffert, Eva, additional, Van Nechel, Christian, additional, Langmann, Thomas, additional, Deconinck, Nicolas, additional, and De Baere, Elfride, additional

Published
2015
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48. Submicroscopic Deletions at 13q32.1 Cause Congenital Microcoria

Author

Fares-Taie, Lucas, primary, Gerber, Sylvie, additional, Tawara, Akihiko, additional, Ramirez-Miranda, Arturo, additional, Douet, Jean-Yves, additional, Verdin, Hannah, additional, Guilloux, Antoine, additional, Zenteno, Juan C., additional, Kondo, Hiroyuki, additional, Moisset, Hugo, additional, Passet, Bruno, additional, Yamamoto, Ken, additional, Iwai, Masaru, additional, Tanaka, Toshihiro, additional, Nakamura, Yusuke, additional, Kimura, Wataru, additional, Bole-Feysot, Christine, additional, Vilotte, Marthe, additional, Odent, Sylvie, additional, Vilotte, Jean-Luc, additional, Munnich, Arnold, additional, Regnier, Alain, additional, Chassaing, Nicolas, additional, De Baere, Elfride, additional, Raymond-Letron, Isabelle, additional, Kaplan, Josseline, additional, Calvas, Patrick, additional, Roche, Olivier, additional, and Rozet, Jean-Michel, additional

Published
2015
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49. Homozygous deletion of glutamate receptor gene GRID2 causes new hotfoot mutant phenotype, characterized by early-onset cerebellar ataxia and retinal dystrophy

Author

Van Schil, Kristof, Karlstetter, Marcus, Meire, Francoise, Bauwens, Miriam, Verdin, Hannah, Coppieters, Frauke, Scheiffert, Eva, Deconinck, Nicolas, Langmann, Thomas, De Baere, Elfride, Van Schil, Kristof, Karlstetter, Marcus, Meire, Francoise, Bauwens, Miriam, Verdin, Hannah, Coppieters, Frauke, Scheiffert, Eva, Deconinck, Nicolas, Langmann, Thomas, and De Baere, Elfride

Published
2014

50. Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion.

Author

Van Schil, Kristof, Meire, Françoise, Karlstetter, Marcus, Bauwens, Miriam, Verdin, Hannah, Coppieters, Frauke, Scheiffert, Eva, Van Nechel, Christian, Langmann, Thomas, Deconinck, Nicolas, De Baere, Elfride, Van Schil, Kristof, Meire, Françoise, Karlstetter, Marcus, Bauwens, Miriam, Verdin, Hannah, Coppieters, Frauke, Scheiffert, Eva, Van Nechel, Christian, Langmann, Thomas, Deconinck, Nicolas, and De Baere, Elfride

Abstract

Purpose:The aim of this study was to identify the genetic cause of early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy in a consanguineous family.Methods:An affected 6-month-old child underwent neurological and ophthalmological examinations. Genetic analyses included homozygosity mapping, copy number analysis, conventional polymerase chain reaction, Sanger sequencing, quantitative polymerase chain reaction, and whole-exome sequencing. Expression analysis of GRID2 was performed by quantitative polymerase chain reaction and immunohistochemistry.Results:A homozygous deletion of exon 2 of GRID2 (p.Gly30_Glu81del) was identified in the proband. GRID2 encodes an ionotropic glutamate receptor known to be selectively expressed in cerebellar Purkinje cells. Here, we demonstrated GRID2 expression in human adult retina and retinal pigment epithelium. In addition, Grid2 expression was demonstrated in different stages of murine retinal development. GRID2 immunostaining was shown in murine and human retina. Whole-exome sequencing in the proband did not provide arguments for other disease-causing mutations, supporting the idea that the phenotype observed represents a single clinical entity.Conclusion:We identified GRID2 as an underlying disease gene of early-onset autosomal recessive cerebellar ataxia with retinal dystrophy, expanding the clinical spectrum of GRID2 deletion mutants. We demonstrated for the first time GRID2 expression and localization in human and murine retina, providing evidence for a novel functional role of GRID2 in the retina.Genet Med advance online publication 14 August 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.95., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2014

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