Author: "UCL - (SLuc) Centre de génétique médicale UCL" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"UCL - (SLuc) Centre de génétique médicale UCL"' showing total 380 results

Start Over Author "UCL - (SLuc) Centre de génétique médicale UCL"

380 results on '"UCL - (SLuc) Centre de génétique médicale UCL"'

1. Epithelioid Fibrous Histiocytoma with CARS-ALK Fusion: First Case Report

Author: UCL - (SLuc) Service d'anatomie pathologique, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service de dermatologie, UCL - (SLuc) Centre de génétique médicale UCL, Secco, Léo-Paul, Libbrecht, Louis, Seijnhaeve, Elsa, Eggers, Silke, Dekairelle, Anne-France, De Roo, An-Katrien, UCL - (SLuc) Service d'anatomie pathologique, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service de dermatologie, UCL - (SLuc) Centre de génétique médicale UCL, Secco, Léo-Paul, Libbrecht, Louis, Seijnhaeve, Elsa, Eggers, Silke, Dekairelle, Anne-France, and De Roo, An-Katrien
Abstract: Epithelioid fibrous histiocytoma (EFH) is a type of uncommon skin tumor mostly harboring Anaplastic Lymphoma Kinase (ALK) gene rearrangement, with different fusion partners reported. Whether this tumor is a separate entity or has a relationship with conventional fibrous histiocytomas is still a matter of debate. Benign course is the rule after complete surgical excision. A rare subtype of EFH with fusiform cells has been described, with specific fusion partners. Inflammatory myofibroblastic tumor (IMT) is a type of soft tissue tumor rarer than EFH, and it can display distant metastases. Some cases of primary cutaneous IMT included two with Cysteinyl-tRNA Synthetase 1 (CARS)-ALK rearrangement. IMT can have the same fusion partners as EFH, such as DCTN1, TMP3 or EML4 genes. We report the case of a 42-year-old woman presenting EFH with fusiform morphology harboring CARS-ALK fusion and discuss similarities and differences with IMT.
Published: 2023

2. Exceptional manifestation of Madelung's disease after liver transplantation.

Author: UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service de chirurgie plastique, UCL - SSS/IREC/MORF - Pôle de Morphologie, UCL - (SLuc) Service de chirurgie et transplantation abdominale, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de gastro-entérologie, Lentini, Audrey, Ciccarelli, Olga, Bonaccorsi Riani, Eliano, Coubeau, Laurent, Revencu, Nicole, Dahlqvist, Géraldine, Lengelé, Benoît, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service de chirurgie plastique, UCL - SSS/IREC/MORF - Pôle de Morphologie, UCL - (SLuc) Service de chirurgie et transplantation abdominale, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de gastro-entérologie, Lentini, Audrey, Ciccarelli, Olga, Bonaccorsi Riani, Eliano, Coubeau, Laurent, Revencu, Nicole, Dahlqvist, Géraldine, and Lengelé, Benoît
Abstract: Unlike simple obesity, Madelung's disease (MD) is a rare disease characterized by symmetric accumulation of massive adipose tissue on the neck, the superior part of the trunk and limbs, leading to a pathognomonic cosmetic deformity. Here, we report an extremely rare case of MD associated with bilateral gynecomastia in a 61-year-old man, with a history of recent liver transplantation for alcoholic liver disease (ALD).
Published: 2022

3. Postallograft aleukemic mast cell leukemia, with macrophagic activation syndrome

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de biologie hématologique, UCL - (SLuc) Centre de génétique médicale UCL, Hamdash, Salwa, Deckers, Corentin, Chapelle, Virginie, Vanderdonck, Martin, Saussoy, Pascale, Rousseaux, Madeleine, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de biologie hématologique, UCL - (SLuc) Centre de génétique médicale UCL, Hamdash, Salwa, Deckers, Corentin, Chapelle, Virginie, Vanderdonck, Martin, Saussoy, Pascale, and Rousseaux, Madeleine
Published: 2022

4. Somatic TEK variant with intraarticular venous malformation and knee hemarthrosis treated with rapamycin.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de génétique médicale UCL, Adham, Salma, Revencu, Nicole, Mestre, Sandrine, Nou-Howaldt, Monira, Vernhet-Kovacsik, Hélène, Quéré, Isabelle, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de génétique médicale UCL, Adham, Salma, Revencu, Nicole, Mestre, Sandrine, Nou-Howaldt, Monira, Vernhet-Kovacsik, Hélène, and Quéré, Isabelle
Abstract: Venous malformations (VMs) are the most common vascular anomalies and have been associated with somatic variants in TEK. Current treatment of VM joint component might be challenging due to the size or location of some lesions or ineffective with recurrence of malformed veins. Targeted molecular therapies after identification of genetic defects might be an alternative. We report a case with intraarticular bleeding due to VM with a TEK pathogenic somatic variant treated with rapamycin. A 26-year-old female patient was evaluated for right calf pain secondary to venous malformation of the right inferior limb with an intraarticular component in the right knee. Hemarthrosis and degenerative chondropathy of the knee were evidenced at MRA. Molecular diagnosis evidenced a pathogenic somatic TEK variant. Rapamycin was introduced to stop bleeding, with good tolerance and efficacy. The TEK receptor signals through the PI3K/AKT/mTOR pathway and TEK mutations have been linked to AKT activation. As rapamycin acts against angiogenesis and reduces phosphorylated-AKT levels, targeted molecular therapy should be discussed as first-line therapy in patients with proven molecular diagnosis and diffuse VM inaccessible to conventional treatment.
Published: 2022

5. Fetal Vesicoallantoic Cyst and Intraabdominal Defects: An Unusual Case and Review of the Literature

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, UCL - SST/ELI/ELIE - Environmental Sciences, UCL - SSS/DDUV/CELL - Biologie cellulaire, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre labio-palatin Albert de Coninck, UCL - (SLuc) Service d'obstétrique, Delvaux, Mathieu, Sznajer, Yves, Marbaix, Etienne, Biard, Jean Marc, Hubinont, Corinne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, UCL - SST/ELI/ELIE - Environmental Sciences, UCL - SSS/DDUV/CELL - Biologie cellulaire, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre labio-palatin Albert de Coninck, UCL - (SLuc) Service d'obstétrique, Delvaux, Mathieu, Sznajer, Yves, Marbaix, Etienne, Biard, Jean Marc, and Hubinont, Corinne
Abstract: no abstract available
Published: 2022

6. Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, Tessadori, Federico, Duran, Karen, Knapp, Karen, Fellner, Matthias, Deciphering Developmental Disorders Study, Smithson, Sarah, Beleza Meireles, Ana, Elting, Mariet W, Waisfisz, Quinten, O'Donnell-Luria, Anne, Nowak, Catherine, Douglas, Jessica, Ronan, Anne, Brunet, Theresa, Kotzaeridou, Urania, Svihovec, Shayna, Saenz, Margarita S, Thiffault, Isabelle, Del Viso, Florencia, Devine, Patrick, Rego, Shannon, Tenney, Jessica, van Haeringen, Arie, Ruivenkamp, Claudia A L, Koene, Saskia, Robertson, Stephen P, Deshpande, Charulata, Pfundt, Rolph, Verbeek, Nienke, van de Kamp, Jiddeke M, Weiss, Janneke M M, Ruiz, Anna, Gabau, Elisabeth, Banne, Ehud, Pepler, Alexander, Bottani, Armand, Laurent, Sacha, Guipponi, Michel, Bijlsma, Emilia, Bruel, Ange-Line, Sorlin, Arthur, Willis, Mary, Powis, Zoe, Smol, Thomas, Vincent-Delorme, Catherine, Baralle, Diana, Colin, Estelle, Revencu, Nicole, Calpena, Eduardo, Wilkie, Andrew O M, Chopra, Maya, Cormier-Daire, Valerie, Keren, Boris, Afenjar, Alexandra, Niceta, Marcello, Terracciano, Alessandra, Specchio, Nicola, Tartaglia, Marco, Rio, Marlene, Barcia, Giulia, Rondeau, Sophie, Colson, Cindy, Bakkers, Jeroen, Mace, Peter D, Bicknell, Louise S, van Haaften, Gijs, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, Tessadori, Federico, Duran, Karen, Knapp, Karen, Fellner, Matthias, Deciphering Developmental Disorders Study, Smithson, Sarah, Beleza Meireles, Ana, Elting, Mariet W, Waisfisz, Quinten, O'Donnell-Luria, Anne, Nowak, Catherine, Douglas, Jessica, Ronan, Anne, Brunet, Theresa, Kotzaeridou, Urania, Svihovec, Shayna, Saenz, Margarita S, Thiffault, Isabelle, Del Viso, Florencia, Devine, Patrick, Rego, Shannon, Tenney, Jessica, van Haeringen, Arie, Ruivenkamp, Claudia A L, Koene, Saskia, Robertson, Stephen P, Deshpande, Charulata, Pfundt, Rolph, Verbeek, Nienke, van de Kamp, Jiddeke M, Weiss, Janneke M M, Ruiz, Anna, Gabau, Elisabeth, Banne, Ehud, Pepler, Alexander, Bottani, Armand, Laurent, Sacha, Guipponi, Michel, Bijlsma, Emilia, Bruel, Ange-Line, Sorlin, Arthur, Willis, Mary, Powis, Zoe, Smol, Thomas, Vincent-Delorme, Catherine, Baralle, Diana, Colin, Estelle, Revencu, Nicole, Calpena, Eduardo, Wilkie, Andrew O M, Chopra, Maya, Cormier-Daire, Valerie, Keren, Boris, Afenjar, Alexandra, Niceta, Marcello, Terracciano, Alessandra, Specchio, Nicola, Tartaglia, Marco, Rio, Marlene, Barcia, Giulia, Rondeau, Sophie, Colson, Cindy, Bakkers, Jeroen, Mace, Peter D, Bicknell, Louise S, and van Haaften, Gijs
Abstract: Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.
Published: 2022

7. Further delineation of auriculocondylar syndrome based on 14 novel cases and reassessment of 25 published cases.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de génétique médicale UCL, Vegas, Nancy, Demir, Zeynep, Gordon, Christopher T, Breton, Sylvain, Romanelli Tavares, Vanessa L, Moisset, Hugo, Zechi-Ceide, Roseli, Kokitsu-Nakata, Nancy M, Kido, Yasuhiro, Marlin, Sandrine, Gherbi Halem, Souad, Meerschaut, Ilse, Callewaert, Bert, Chung, Brian, Revencu, Nicole, Lehalle, Daphné, Petit, Florence, Propst, Evan J, Papsin, Blake C, Phillips, John H, Jakobsen, Linda, Le Tanno, Pauline, Thévenon, Julien, McGaughran, Julie, Gerkes, Erica H, Leoni, Chiara, Kroisel, Peter, Tan, Tiong Y, Henderson, Alex, Terhal, Paulien, Basel-Salmon, Lina, Alkindy, Adila, White, Susan M, Passos-Bueno, Maria R, Pingault, Véronique, De Pontual, Loïc, Amiel, Jeanne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de génétique médicale UCL, Vegas, Nancy, Demir, Zeynep, Gordon, Christopher T, Breton, Sylvain, Romanelli Tavares, Vanessa L, Moisset, Hugo, Zechi-Ceide, Roseli, Kokitsu-Nakata, Nancy M, Kido, Yasuhiro, Marlin, Sandrine, Gherbi Halem, Souad, Meerschaut, Ilse, Callewaert, Bert, Chung, Brian, Revencu, Nicole, Lehalle, Daphné, Petit, Florence, Propst, Evan J, Papsin, Blake C, Phillips, John H, Jakobsen, Linda, Le Tanno, Pauline, Thévenon, Julien, McGaughran, Julie, Gerkes, Erica H, Leoni, Chiara, Kroisel, Peter, Tan, Tiong Y, Henderson, Alex, Terhal, Paulien, Basel-Salmon, Lina, Alkindy, Adila, White, Susan M, Passos-Bueno, Maria R, Pingault, Véronique, De Pontual, Loïc, and Amiel, Jeanne
Abstract: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.
Published: 2022

8. Survival outcomes after neoadjuvant letrozole and palbociclib versus third generation chemotherapy for patients with high-risk oestrogen receptor-positive HER2-negative breast cancer.

Author: UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Centre de génétique médicale UCL, Delaloge, Suzette, Dureau, Sylvain, D'Hondt, Véronique, Desmoulins, Isabelle, Heudel, Pierre-Etienne, Duhoux, Francois P, Levy, Christelle, Lerebours, Florence, Mouret-Reynier, Marie A, Dalenc, Florence, Frenel, Jean-Sébastien, Jouannaud, Christelle, Venat-Bouvet, Laurence, Nguyen, Suzanne, Callens, Cécile, Gentien, David, Rapinat, Audrey, Manduzio, Helene, Vincent-Salomon, Anne, Lemonnier, Jérôme, Cottu, Paul, French Breast cancer Intergroup Unicancer-UCBG, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Centre de génétique médicale UCL, Delaloge, Suzette, Dureau, Sylvain, D'Hondt, Véronique, Desmoulins, Isabelle, Heudel, Pierre-Etienne, Duhoux, Francois P, Levy, Christelle, Lerebours, Florence, Mouret-Reynier, Marie A, Dalenc, Florence, Frenel, Jean-Sébastien, Jouannaud, Christelle, Venat-Bouvet, Laurence, Nguyen, Suzanne, Callens, Cécile, Gentien, David, Rapinat, Audrey, Manduzio, Helene, Vincent-Salomon, Anne, Lemonnier, Jérôme, Cottu, Paul, and French Breast cancer Intergroup Unicancer-UCBG
Abstract: Besides their development as additional adjuvant treatments, CDK4/6 inhibitors combined with endocrine therapy could represent less toxic alternatives to chemotherapy in postmenopausal women with high-risk oestrogen receptor-positive, HER2-negative breast cancer currently a candidate for chemotherapy. The multicentre, international, randomised phase 2 NEOPAL trial showed that the letrozole-palbociclib combination led to clinical and pathological responses equivalent to sequential anthracycline-taxanes chemotherapy. Secondary objectives included survival outcomes. Secondary end-points of NEOPAL included progression-free survival (PFS) and invasive-disease free survival (iDFS) in the intent-to-treat population. Exploratory end-points were overall survival (OS) and breast cancer specific survival (BCSS) in the intent-to-treat population, as well as iDFS, OS and BCSS according to the administration of chemotherapy. Hundred and six patients were randomised. Pathological complete response rates were 3.8% and 5.9%. Twenty-three of the 53 patients in the letrozole-palbociclib arm received postoperative adjuvant chemotherapy. At a median follow-up of 40.4 months [0-56.6], 11 progressions have been observed, of which three were in the letrozole-palbociclib and 8 in the control arm. PFS (HR = 1.01; [95%CI 0.36-2.90], p = 0.98) and iDFS (HR = 0.83; [95%CI 0.31-2.23], p = 0.71) did not differ between both arms. The 40 months PFS rate was 86.7% [95%CI 78.0-96.4] and 89.9% [95%CI 81.8-98.7] in letrozole-palbociclib and control arms, respectively. Outcomes of patients who did not receive chemotherapy were not statistically different from those who received it. NEOPAL suggests that a neoadjuvant letrozole-palbociclib strategy may allow sparing chemotherapy in some patients with luminal breast cancer while allowing good long-term outcomes. Larger confirmatory studies are needed.
Published: 2022

9. Lessons for the clinical nephrologist: lumasiran as the future cornerstone treatment for patients with primary hyperoxaluria type 1?

Author: UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de microbiologie, UCL - (SLuc) Département de pédiatrie, UCL - (SLuc) Service de pédiatrie générale, Gillion, Valentine, Dahan, Karin, Scohy, Anaïs, Devresse, Arnaud, Godefroid, Nathalie, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de microbiologie, UCL - (SLuc) Département de pédiatrie, UCL - (SLuc) Service de pédiatrie générale, Gillion, Valentine, Dahan, Karin, Scohy, Anaïs, Devresse, Arnaud, and Godefroid, Nathalie
Published: 2022

10. FC044: Heterozygous Variants in Kinase Domain of NEK8 cause an Autosomal-Dominant Ciliopathy

Author: UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (MGD) Service de néphrologie, Claus, Laura, Stallworth, Jennifer, van Jaarsveld, Richard, Turner, Joshu, Hawks, Alexandra, May, Melanie, Flanagan-Steet, Heather, Louie, Raymond, Silver, Josh, Lerner-Ellise, Jordan, Morel, Chantal, Mighton, Chloe, Ziegler, Alban, Barakat, Stefan, Dahan, Karin, Demoulin, Nathalie, Goffin, Eric, Larsen, Martin, Michael Hertz, Jens, Lilien, Marc, Olinger, Eric, Sayer, John, Obeidová, Lena, Seeman, Tomas, Senum, Sarah, Hanna, Christian, Rogers, Curtis, Duran, Karen, Peters, Edith, Harris, Peter, Mason, Jennifer, van Haaften, Gijs, M. Van Eerde, Albertien, Steet, Richard, UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (MGD) Service de néphrologie, Claus, Laura, Stallworth, Jennifer, van Jaarsveld, Richard, Turner, Joshu, Hawks, Alexandra, May, Melanie, Flanagan-Steet, Heather, Louie, Raymond, Silver, Josh, Lerner-Ellise, Jordan, Morel, Chantal, Mighton, Chloe, Ziegler, Alban, Barakat, Stefan, Dahan, Karin, Demoulin, Nathalie, Goffin, Eric, Larsen, Martin, Michael Hertz, Jens, Lilien, Marc, Olinger, Eric, Sayer, John, Obeidová, Lena, Seeman, Tomas, Senum, Sarah, Hanna, Christian, Rogers, Curtis, Duran, Karen, Peters, Edith, Harris, Peter, Mason, Jennifer, van Haaften, Gijs, M. Van Eerde, Albertien, and Steet, Richard
Published: 2022

11. Artificial increase of uracilemia during fluoropyrimidine treatment can lead to DPD deficiency misinterpretation.

Author: UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Centre de toxicologie clinique, UCL - (SLuc) Centre de génétique médicale UCL, Thomas, F, Maillard, M, Launay, M, Tron, C, Etienne-Grimaldi, M-C, Gautier-Veyret, E, Haufroid, V, Pallet, N, Royer, B, Narjoz, C, Schmitt, A, Groupe de Pharmacologie Clinique Oncologique (GPCO-UNICANCER), UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Centre de toxicologie clinique, UCL - (SLuc) Centre de génétique médicale UCL, Thomas, F, Maillard, M, Launay, M, Tron, C, Etienne-Grimaldi, M-C, Gautier-Veyret, E, Haufroid, V, Pallet, N, Royer, B, Narjoz, C, Schmitt, A, and Groupe de Pharmacologie Clinique Oncologique (GPCO-UNICANCER)
Abstract: No abstract available
Published: 2021

12. Mutation in the Gene: A New Family with Familial Renal Hypouricemia Type 2.

Author: UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, UCL - (SLuc) Centre de génétique médicale UCL, Maalouly, Christian, Dahan, Karin, Devresse, Arnaud, Gillion, Valentine, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, UCL - (SLuc) Centre de génétique médicale UCL, Maalouly, Christian, Dahan, Karin, Devresse, Arnaud, and Gillion, Valentine
Abstract: Familial renal hypouricemia is a rare genetic disorder characterized by a defect in renal tubular urate reabsorption. Some patients present with exercise-induced acute kidney injury and nephrolithiasis. Type II is caused by mutations in the gene. Here, we report the case of a young patient who developed acute kidney injury after exercise secondary to familial renal hypouricemia type II. The same mutation was found in other asymptomatic members of his family. We review the medical literature on this condition. This case highlights the importance of considering uric acid disorders in the work-up of acute kidney injury after exercise.
Published: 2021

13. Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Futema, Marta, Ramaswami, Uma, Tichy, Lukas, Bogsrud, Martin P, Holven, Kirsten B, Roeters van Lennep, Jeanine, Wiegman, Albert, Descamps, Olivier S, De Leener, Anne, Fastre, Elodie, Vrablik, Michal, Freiberger, Tomas, Esterbauer, Harald, Dieplinger, Hans, Greber-Platzer, Susanne, Medeiros, Ana M, Bourbon, Mafalda, Mollaki, Vasiliki, Drogari, Euridiki, Humphries, Steve E, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Futema, Marta, Ramaswami, Uma, Tichy, Lukas, Bogsrud, Martin P, Holven, Kirsten B, Roeters van Lennep, Jeanine, Wiegman, Albert, Descamps, Olivier S, De Leener, Anne, Fastre, Elodie, Vrablik, Michal, Freiberger, Tomas, Esterbauer, Harald, Dieplinger, Hans, Greber-Platzer, Susanne, Medeiros, Ana M, Bourbon, Mafalda, Mollaki, Vasiliki, Drogari, Euridiki, and Humphries, Steve E
Abstract: Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece. Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests. Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l). The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH.
Published: 2021

14. Performance and Diagnostic Value of Genome-Wide Noninvasive Prenatal Testing in Multiple Gestations.

Author: UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, van Riel, Margot, Brison, Nathalie, Baetens, Machteld, Blaumeiser, Bettina, Boemer, François, Bourlard, Laura, Bulk, Saskia, De Leener, Anne, Désir, Julie, Devriendt, Koenraad, Dheedene, Annelies, Duquenne, Armelle, Fieremans, Nathalie, Fieuw, Annelies, Gatot, Jean-Stéphane, Grisart, Bernard, Janssens, Sandra, Khudashvili, Naïri, Lannoo, Lore, Marichal, Axel, Meunier, Colombine, Palmeira, Leonor, Parijs, Ilse, Pichon, Bruno, Roets, Ellen, Sammels, Eva, Smits, Guillaume, Suenaert, Marion, Sznajer, Yves, Van den Bogaert, Kris, Vancoillie, Leen, Vandeputte, Lotte, Vantroys, Elise, Vermeesch, Joris Robert, Janssens, Katrien, UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, van Riel, Margot, Brison, Nathalie, Baetens, Machteld, Blaumeiser, Bettina, Boemer, François, Bourlard, Laura, Bulk, Saskia, De Leener, Anne, Désir, Julie, Devriendt, Koenraad, Dheedene, Annelies, Duquenne, Armelle, Fieremans, Nathalie, Fieuw, Annelies, Gatot, Jean-Stéphane, Grisart, Bernard, Janssens, Sandra, Khudashvili, Naïri, Lannoo, Lore, Marichal, Axel, Meunier, Colombine, Palmeira, Leonor, Parijs, Ilse, Pichon, Bruno, Roets, Ellen, Sammels, Eva, Smits, Guillaume, Suenaert, Marion, Sznajer, Yves, Van den Bogaert, Kris, Vancoillie, Leen, Vandeputte, Lotte, Vantroys, Elise, Vermeesch, Joris Robert, and Janssens, Katrien
Abstract: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies. We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort. Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies. Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations.
Published: 2021

15. Insight into the bacterial communities of the subterranean aphid Anoecia corni.

Author: UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique), UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de l'allergie, Fakhour, Samir, Renoz, François, Ambroise, Jérôme, Pons, Inès, Noël, Christine, Gala, Jean-Luc, Hance, Thierry, UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique), UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de l'allergie, Fakhour, Samir, Renoz, François, Ambroise, Jérôme, Pons, Inès, Noël, Christine, Gala, Jean-Luc, and Hance, Thierry
Abstract: Many insect species are associated with bacterial partners that can significantly influence their evolutionary ecology. Compared to other insect groups, aphids harbor a bacterial microbiota that has the reputation of being poorly diversified, generally limited to the presence of the obligate nutritional symbiont Buchnera aphidicola and some facultative symbionts. In this study, we analyzed the bacterial diversity associated with the dogwood-grass aphid Anoecia corni, an aphid species that spends much of its life cycle in a subterranean environment. Little is known about the bacterial diversity associated with aphids displaying such a lifestyle, and one hypothesis is that close contact with the vast microbial community of the rhizosphere could promote the acquisition of a richer bacterial diversity compared to other aphid species. Using 16S rRNA amplicon Illumina sequencing on specimens collected on wheat roots in Morocco, we identified 10 bacterial operational taxonomic units (OTUs) corresponding to five bacterial genera. In addition to the obligate symbiont Buchnera, we identified the facultative symbionts Serratia symbiotica and Wolbachia in certain aphid colonies. The detection of Wolbachia is unexpected as it is considered rare in aphids. Moreover, its biological significance remains unknown in these insects. Besides, we also detected Arsenophonus and Dactylopiibacterium carminicum. These results suggest that, despite its subterranean lifestyle, A. corni shelter a bacterial diversity mainly limited to bacterial endosymbionts.
Published: 2021

16. Optimized DNA-based identification of Toxocara spp. eggs in soil and sand samples.

Author: UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique), UCL - (SLuc) Centre de l'allergie, UCL - (SLuc) Centre de génétique médicale UCL, Jarosz, Wojciech, Durant, Jean-Francois, Irenge, Leonid Mwana Wa Bene, Fogt-Wyrwas, Renata, Mizgajska-Wiktor, Hanna, Gala, Jean-Luc, UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique), UCL - (SLuc) Centre de l'allergie, UCL - (SLuc) Centre de génétique médicale UCL, Jarosz, Wojciech, Durant, Jean-Francois, Irenge, Leonid Mwana Wa Bene, Fogt-Wyrwas, Renata, Mizgajska-Wiktor, Hanna, and Gala, Jean-Luc
Abstract: Toxocara canis and Toxocara cati are globally distributed roundworms and causative agents of human toxocariasis, via ingestion of Toxocara eggs. Control of Toxocara infections is constrained by a lack of sensitive methods for screening of animal faeces and environmental samples potentially contaminated by Toxocara eggs. In this work, a pre-analytical method for efficient extraction of DNA from Toxocara eggs in environmental samples was set up using our previously validated T. canis- and T. cati-specific quantitative real-time polymerase chain reaction (qPCR). For this purpose, the influence of different methods for egg lysis, DNA extraction and purification for removal of PCR inhibitors were assessed on environmental samples. To select the best egg disruption method, six protocols were compared on pure T. canis egg suspensions, including enzymatic lysis and thermal or mechanical disruption. Based on the selected best method, an analytical workflow was set up to compare two DNA extraction methods (FastDNA™ SPIN Kit for Soil versus DNeasy PowerMax Soil Kit) with an optional dilution and/or clean-up (Agencourt AMPure) step. This workflow was evaluated on 10-g soil and 10-g sand samples spiked with egg suspensions of T. canis (tenfold dilutions of 10 eggs in triplicate). The capacity of the different methods, used alone or in combination, to increase the ratio of positive tests was assessed. The resulting optimal workflow for processing spiked soil samples was then tested on environmental soil samples and compared with the conventional flotation-centrifugation and microscopic examination of Toxocara eggs. The most effective DNA extraction method for Toxocara eggs in soil samples consisted in the combination of mechanical lysis of eggs using beads, followed by DNA extraction with the DNeasy PowerMax Soil Kit, and completed with an additional DNA clean-up step with AMPure beads and a sample DNA dilution (1:10). This workflow exhibited a limit of detection of 4 and 46 T. c
Published: 2021

17. Osteogenesis imperfecta phenotypes resulting from serine for glycine substitutions in the alpha2(I) collagen chain

Author: UCL - (SLuc) Centre de génétique médicale UCL, Nuytinck, Lieve, Wettinck, Karen, Freund, Margarida, Van Maldergem, Lionel, Fabry, Guy, De Paepe, Anne, UCL - (SLuc) Centre de génétique médicale UCL, Nuytinck, Lieve, Wettinck, Karen, Freund, Margarida, Van Maldergem, Lionel, Fabry, Guy, and De Paepe, Anne
Abstract: Clinical and biochemical findings in 5 unrelated patients with osteogenesis imperfecta (OI) with a serine for glycine substitution in the alpha2(I) collagen chain are presented. The data are compared to other serine substitutions in collagen type I. Findings show that the phenotypic severity of serine for glycine substitutions in the alpha2(I) collagen chain is region dependent similar to the observations for the alpha1(I) collagen chain, and that so-called 'lethal' and 'non-lethal' domains in the alpha1 and alpha2 collagen chains do not necessarily correspond.
Published: 2021

18. A simple and fast spectroscopy-based technique for Covid-19 diagnosis

Author: UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique), UCL - (SLuc) Centre de l'allergie, UCL - (SLuc) Centre de génétique médicale UCL, Kitane, Driss Lahlou, Loukman, Salma, Marchoudi, Nabila, Fernandez-Galiana, Alvaro, El Ansari, Fatima Zahra, Jouali, Farah, Badir, Jamal, Gala, Jean-Luc, Bertsimas, Dimitris, Azami, Nawfal, Lakbita, Omar, Moudam, Omar, Benhida, Rachid, Fekkak, Jamal, UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique), UCL - (SLuc) Centre de l'allergie, UCL - (SLuc) Centre de génétique médicale UCL, Kitane, Driss Lahlou, Loukman, Salma, Marchoudi, Nabila, Fernandez-Galiana, Alvaro, El Ansari, Fatima Zahra, Jouali, Farah, Badir, Jamal, Gala, Jean-Luc, Bertsimas, Dimitris, Azami, Nawfal, Lakbita, Omar, Moudam, Omar, Benhida, Rachid, and Fekkak, Jamal
Abstract: The coronavirus pandemic, which appeared in Wuhan, China, in December 2019, rapidly spread all over the world in only a few weeks. Faster testing techniques requiring less resources are key in managing the pandemic, either to enable larger scale testing or even just provide developing countries with limited resources, particularly in Africa, means to perform tests to manage the crisis. Here, we report an unprecedented, rapid, reagent-free and easy-to-use screening spectroscopic method for the detection of SARS-CoV-2 on RNA extracts. This method, validated on clinical samples collected from 280 patients with quantitative predictive scores on both positive and negative samples, is based on a multivariate analysis of FTIR spectra of RNA extracts. This technique, in agreement with RT-PCR, achieves 97.8% accuracy, 97% sensitivity and 98.3% specificity while reducing the testing time post RNA extraction from hours to minutes. Furthermore, this technique can be used in several laboratories with limited resources.
Published: 2021

19. Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia.

Author: UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, Costantini, Alice, Alm, Jessica J, Tonelli, Francesca, Valta, Helena, Huber, Céline, Tran, Anh N, Daponte, Valentina, Kirova, Nadi, Kwon, Yong-Uk, Bae, Jung Yun, Chung, Woo Yeong, Tan, Shengjiang, Sznajer, Yves, Nishimura, Gen, Näreoja, Tuomas, Warren, Alan J, Cormier-Daire, Valérie, Kim, Ok-Hwa, Forlino, Antonella, Cho, Tae-Joon, Mäkitie, Outi, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, Costantini, Alice, Alm, Jessica J, Tonelli, Francesca, Valta, Helena, Huber, Céline, Tran, Anh N, Daponte, Valentina, Kirova, Nadi, Kwon, Yong-Uk, Bae, Jung Yun, Chung, Woo Yeong, Tan, Shengjiang, Sznajer, Yves, Nishimura, Gen, Näreoja, Tuomas, Warren, Alan J, Cormier-Daire, Valérie, Kim, Ok-Hwa, Forlino, Antonella, Cho, Tae-Joon, and Mäkitie, Outi
Abstract: Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with SEMD in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families, we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation-positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient-derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p < 0.001). Cellular functional defects in fibroblasts from mutation-positive subjects indicated a significant increase in the ratio of 60S subunits to 80S ribosomes (p = 0.007) and attenuated global translation (p = 0.017). In line with the human phenotype, our rpl13 mutant zebrafish model, generated by CRISPR-Cas9 editing, showed cartilage deformities at embryonic and juvenile stages. These findings extend the genetic spectrum of RPL13 mutations causing this novel human ribosomopathy with variable skeletal features. Our study underscores for the first time incomplete penetrance and broad phenotypic variability in SEMD-RPL13 type and confirms impaired ribosomal function. Furthermore, the newly generated rpl13 mutant zebrafish model corroborates the role of eL13 in skeletogenesis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
Published: 2021

20. Frequency of Participation in External Quality Assessment Programs Focused on Rare Diseases: Belgian Guidelines for Human Genetics Centers.

Author: UCL - SSS/DDUV/GEHU - Génétique, UCL - (SLuc) Centre de génétique médicale UCL, Lantoine, Joséphine, Brysse, Anne, Dideberg, Vinciane, Claes, Kathleen, Symoens, Sofie, Coucke, Wim, Benoit, Valérie, Rombout, Sonia, De Rycke, Martine, Seneca, Sara, Van Laer, Lut, Wuyts, Wim, Corveleyn, Anniek, Van Den Bogaert, Kris, Rydlewski, Catherine, Wilkin, Françoise, Ravoet, Marie, Fastré, Elodie, Capron, Arnaud, Vandevelde, Nathalie Monique, UCL - SSS/DDUV/GEHU - Génétique, UCL - (SLuc) Centre de génétique médicale UCL, Lantoine, Joséphine, Brysse, Anne, Dideberg, Vinciane, Claes, Kathleen, Symoens, Sofie, Coucke, Wim, Benoit, Valérie, Rombout, Sonia, De Rycke, Martine, Seneca, Sara, Van Laer, Lut, Wuyts, Wim, Corveleyn, Anniek, Van Den Bogaert, Kris, Rydlewski, Catherine, Wilkin, Françoise, Ravoet, Marie, Fastré, Elodie, Capron, Arnaud, and Vandevelde, Nathalie Monique
Abstract: BACKGROUND: Participation in quality controls, also called external quality assessment (EQA) schemes, is required for the ISO15189 accreditation of the Medical Centers of Human Genetics. However, directives on the minimal frequency of participation in genetic quality control schemes are lacking or too heterogeneous, with a possible impact on health care quality. OBJECTIVE: The aim of this project is to develop Belgian guidelines on the frequency of participation in quality controls for genetic testing in the context of rare diseases. METHODS: A group of experts analyzed 90 EQA schemes offered by accredited providers and focused on analyses used for the diagnosis of rare diseases. On that basis, the experts developed practical recommendations about the minimal frequencies of participation of the Medical Centers of Human Genetics in quality controls and how to deal with poor performances and change management. These guidelines were submitted to the Belgian Accreditation Body and then reviewed and approved by the Belgian College of Human Genetics and Rare Diseases and by the National Institute for Health and Disability Insurance. RESULTS: The guidelines offer a decisional algorithm for the minimal frequency of participation in human genetics EQA schemes. This algorithm has been developed taking into account the scopes of the EQA schemes, the levels of experience, and the annual volumes of the Centers of Human Genetics in the performance of the tests considered. They include three key principles: (1) the recommended annual assessment of all genetic techniques and technological platforms, if possible through EQAs covering the technique, genotyping, and clinical interpretation; (2) the triennial assessment of the genotyping and interpretation of specific germline mutations and pharmacogenomics analyses; and (3) the documentation of actions undertaken in the case of poor performances and the participation to quality control the following year. The use of a Bayesian statist
Published: 2021

21. Antenatal diagnosis of CHARGE syndrome: Prenatal ultrasound findings and crucial role of fetal dysmorphic signs. About a series of 10 cases and review of literature.

Author: UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de radiologie, UCL - (SLuc) Service d'obstétrique, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service de cardiologie pédiatrique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de néonatologie, Biard, Jean-Marc, Payrat, Stéphanie, Clapuyt, Philippe, Barréa, Catherine, Benoit, Valérie, Baldin, Paméla, Bernard, Pierre, Van Grambezen, Bénédicte, Sznajer, Yves, UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de radiologie, UCL - (SLuc) Service d'obstétrique, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service de cardiologie pédiatrique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de néonatologie, Biard, Jean-Marc, Payrat, Stéphanie, Clapuyt, Philippe, Barréa, Catherine, Benoit, Valérie, Baldin, Paméla, Bernard, Pierre, Van Grambezen, Bénédicte, and Sznajer, Yves
Abstract: Although the prognosis of CHARGE syndrome can be highly variable from mild until severe, final diagnosis is difficult to establish in utero. The aim of our study is to compare antenatal and postnatal findings in a retrospective cohort of 10 successive patients with a positive CHD7 gene variant in order to identify the specific prenatal features for CHARGE syndrome diagnosis. Fetal ultrasound, follow-up and supplementary investigations are collected and compared to postnatal findings. Congenital heart defect (7/10), choanal atresia (7/10) and tracheoesophageal atresia (4/10) are the most frequent fetal anomalies found. Inner and external ear anomalies appear as the keystone (constant features) for prenatal diagnosis of CHARGE syndrome in fetuses with multiple anomalies and normal microarray karyotype. External ear malformations are identified in all cases by 3D ultrasound when carefully evaluated. MRI and temporal bone CT-Scan are second line useful tools to assess the diagnosis when looking for semicircular canal agenesis, arhinencephaly and/or choanal atresia. Before availability of prenatal exome sequencing in clinical routine, present findings lead to the recommendation that fetuses, with congenital heart defect (mainly septal and conotruncal), cleft lip/palate or unexplained polyhydramnios should carefully be screened for clues suggesting CHARGE syndrome using 2D and 3D ultrasound, MRI and temporal bone CT-Scan. When CHARGE syndrome is suspected with normal molecular karyotype, CHD7 gene sequencing must be offered.
Published: 2021

22. Outcome of publicly funded nationwide first-tier noninvasive prenatal screening.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Van Den Bogaert, Kris, Lannoo, Lore, Brison, Nathalie, Gatinois, Vincent, Baetens, Machteld, Blaumeiser, Bettina, Boemer, François, Bourlard, Laura, Bours, Vincent, De Leener, Anne, De Rademaeker, Marjan, Désir, Julie, Dheedene, Annelies, Duquenne, Armelle, Fieremans, Nathalie, Fieuw, Annelies, Gatot, Jean-Stéphane, Grisart, Bernard, Janssens, Katrien, Janssens, Sandra, Lederer, Damien, Marichal, Axel, Menten, Björn, Meunier, Colombine, Palmeira, Leonor, Pichon, Bruno, Sammels, Eva, Smits, Guillaume, Sznajer, Yves, Vantroys, Elise, Devriendt, Koenraad, Vermeesch, Joris Robert, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Van Den Bogaert, Kris, Lannoo, Lore, Brison, Nathalie, Gatinois, Vincent, Baetens, Machteld, Blaumeiser, Bettina, Boemer, François, Bourlard, Laura, Bours, Vincent, De Leener, Anne, De Rademaeker, Marjan, Désir, Julie, Dheedene, Annelies, Duquenne, Armelle, Fieremans, Nathalie, Fieuw, Annelies, Gatot, Jean-Stéphane, Grisart, Bernard, Janssens, Katrien, Janssens, Sandra, Lederer, Damien, Marichal, Axel, Menten, Björn, Meunier, Colombine, Palmeira, Leonor, Pichon, Bruno, Sammels, Eva, Smits, Guillaume, Sznajer, Yves, Vantroys, Elise, Devriendt, Koenraad, and Vermeesch, Joris Robert
Abstract: Noninvasive prenatal screening (NIPS) using cell-free DNA has transformed prenatal care. Belgium was the first country to implement and fully reimburse NIPS as a first-tier screening test offered to all pregnant women. A consortium consisting of all Belgian genetic centers report the outcome of two years genome-wide NIPS implementation. The performance for the common trisomies and for secondary findings was evaluated based on 153,575 genome-wide NIP tests. Furthermore, the evolution of the number of invasive tests and the incidence of Down syndrome live births was registered. Trisomies 21, 18, and 13 were detected in respectively 0.32%, 0.07%, and 0.06% of cases, with overall positive predictive values (PPVs) of 92.4%, 84.6%, and 43.9%. Rare autosomal trisomies and fetal segmental imbalances were detected in respectively 0.23% and 0.07% of cases with PPVs of 4.1% and 47%. The number of invasive obstetric procedures decreased by 52%. The number of trisomy 21 live births dropped to 0.04%. Expanding the scope of NIPS beyond trisomy 21 fetal screening allows the implementation of personalized genomic medicine for the obstetric population. This genome-wide NIPS approach has been embedded successfully in prenatal genetic care in Belgium and might serve as a framework for other countries offering NIPS.
Published: 2021

23. A novel RAD21 mutation in a boy with mild Cornelia de Lange presentation: Further delineation of the phenotype.

Author: UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (MGD) Neuropédiatrie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de pédiatrie générale, Dorval, Sarah, Masciadri, Maura, Mathot, Mikaël, Russo, Silvia, Revencu, Nicole, Larizza, Lidia, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (MGD) Neuropédiatrie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de pédiatrie générale, Dorval, Sarah, Masciadri, Maura, Mathot, Mikaël, Russo, Silvia, Revencu, Nicole, and Larizza, Lidia
Abstract: Cornelia de Lange syndrome is a rare autosomal dominant or X-linked developmental disorder characterized by characteristic facial dysmorphism, intellectual disability, growth retardation, upper limb and multiorgan anomalies. Causative mutations have been identified in five genes coding for the cohesion complex structure components or regulatory elements. Among them, RAD21 is associated with a milder phenotype. Very few RAD21 intragenic mutations have been identified so far. Thus, any new patient is a valuable tool to delineate the associated phenotype. We discuss a new patient with RAD21 confirmed molecular diagnosis and compare his clinical features to those of previously described patients carrying different RAD21 intragenic mutations.
Published: 2020

24. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Vissers, Lisenka E L M, Kalvakuri, Sreehari, de Boer, Elke, Geuer, Sinje, Oud, Machteld, van Outersterp, Inge, Kwint, Michael, Witmond, Melde, Kersten, Simone, Polla, Daniel L, Weijers, Dilys, Begtrup, Amber, McWalter, Kirsty, Ruiz, Anna, Gabau, Elisabeth, Morton, Jenny E V, Griffith, Christopher, Weiss, Karin, Gamble, Candace, Bartley, James, Vernon, Hilary J, Brunet, Kendra, Ruivenkamp, Claudia, Kant, Sarina G, Kruszka, Paul, Larson, Austin, Afenjar, Alexandra, Billette de Villemeur, Thierry, Nugent, Kimberly, DDD Study, Raymond, F Lucy, Venselaar, Hanka, Demurger, Florence, Soler-Alfonso, Claudia, Li, Dong, Bhoj, Elizabeth, Hayes, Ian, Hamilton, Nina Powell, Ahmad, Ayesha, Fisher, Rachel, van den Born, Myrthe, Willems, Marjolaine, Sorlin, Arthur, Delanne, Julian, Moutton, Sebastien, Christophe, Philippe, Mau-Them, Frederic Tran, Vitobello, Antonio, Goel, Himanshu, Massingham, Lauren, Phornphutkul, Chanika, Schwab, Jennifer, Keren, Boris, Charles, Perrine, Vreeburg, Maaike, De Simone, Lenika, Hoganson, George, Iascone, Maria, Milani, Donatella, Evenepoel, Lucie, Revencu, Nicole, Ward, D Isum, Burns, Kaitlyn, Krantz, Ian, Raible, Sarah E, Murrell, Jill R, Wood, Kathleen, Cho, Megan T, van Bokhoven, Hans, Muenke, Maximilian, Kleefstra, Tjitske, Bodmer, Rolf, de Brouwer, Arjan P M, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Vissers, Lisenka E L M, Kalvakuri, Sreehari, de Boer, Elke, Geuer, Sinje, Oud, Machteld, van Outersterp, Inge, Kwint, Michael, Witmond, Melde, Kersten, Simone, Polla, Daniel L, Weijers, Dilys, Begtrup, Amber, McWalter, Kirsty, Ruiz, Anna, Gabau, Elisabeth, Morton, Jenny E V, Griffith, Christopher, Weiss, Karin, Gamble, Candace, Bartley, James, Vernon, Hilary J, Brunet, Kendra, Ruivenkamp, Claudia, Kant, Sarina G, Kruszka, Paul, Larson, Austin, Afenjar, Alexandra, Billette de Villemeur, Thierry, Nugent, Kimberly, DDD Study, Raymond, F Lucy, Venselaar, Hanka, Demurger, Florence, Soler-Alfonso, Claudia, Li, Dong, Bhoj, Elizabeth, Hayes, Ian, Hamilton, Nina Powell, Ahmad, Ayesha, Fisher, Rachel, van den Born, Myrthe, Willems, Marjolaine, Sorlin, Arthur, Delanne, Julian, Moutton, Sebastien, Christophe, Philippe, Mau-Them, Frederic Tran, Vitobello, Antonio, Goel, Himanshu, Massingham, Lauren, Phornphutkul, Chanika, Schwab, Jennifer, Keren, Boris, Charles, Perrine, Vreeburg, Maaike, De Simone, Lenika, Hoganson, George, Iascone, Maria, Milani, Donatella, Evenepoel, Lucie, Revencu, Nicole, Ward, D Isum, Burns, Kaitlyn, Krantz, Ian, Raible, Sarah E, Murrell, Jill R, Wood, Kathleen, Cho, Megan T, van Bokhoven, Hans, Muenke, Maximilian, Kleefstra, Tjitske, Bodmer, Rolf, and de Brouwer, Arjan P M
Abstract: CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.
Published: 2020

25. Phenotype description in KIF5C gene hot-spot mutations responsible for malformations of cortical development (MCD).

Author: UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de radiologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de pédiatrie générale, UCL - (SLuc) Service de neurologie pédiatrique, Duquesne, Sophie, Nassogne, Marie-Cécile, Clapuyt, Philippe, Stouffs, Katrien, Sznajer, Yves, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de radiologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de pédiatrie générale, UCL - (SLuc) Service de neurologie pédiatrique, Duquesne, Sophie, Nassogne, Marie-Cécile, Clapuyt, Philippe, Stouffs, Katrien, and Sznajer, Yves
Abstract: Malformations of cortical development (MCD) represent a large group of brain cortical anomalies characterized by distinctive MRI findings. This 'radiologically-based' classification required re evaluation over time on identified underlying mechanisms (cytogenetic and/or molecular). The understanding of genotype findings (nature of cytogenetic/molecular mutation, cellular pathways consequences, timing, …) draw line of evidence on these distinctive group of conditions whereas sometimes precise and constant recurrent genotype/phenotype correlation may not be present. The clinical diagnosis of MCD is often difficult due to variability and rarity of individual types of malformations. Recent studies have established a relationship between lissencephaly and pathogenic variants in genes involved in the kinesin/tubulin pathways, as the KIF5C gene. Pathogenic variants in the KIF5C gene are a more recently discovered cause of severe developmental delay with epilepsy, characterized by specific malformation of cortical development such as pachygyria. Only seven children have been described to date. We report the natural history of a sixteen years old patient identified carrier of a KIF5C gene mutation who developed infantile epilepsy. We then gather phenotype description and molecular results of all reported patients so far in order to better define this entity.
Published: 2020

26. Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Abdelfattah, Fatima, Kariminejad, Ariana, Kahlert, Anne-Karin, Morrison, Patrick J, Gumus, Evren, Mathews, Katherine D, Darbro, Benjamin W, Amor, David J, Walsh, Maie, Sznajer, Yves, Weiß, Luisa, Weidensee, Sabine, Chitayat, David, Shannon, Patrick, Bermejo-Sánchez, Eva, Riaño-Galán, Isolina, Hayes, Ian, Poke, Gemma, Rooryck, Caroline, Pennamen, Perrine, Khung-Savatovsky, Suonavy, Toutain, Annick, Vuillaume, Marie-Laure, Ghaderi-Sohi, Siavash, Kariminejad, Mohamad H, Weinert, Sönke, Sticht, Heinrich, Zenker, Martin, Schanze, Denny, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Abdelfattah, Fatima, Kariminejad, Ariana, Kahlert, Anne-Karin, Morrison, Patrick J, Gumus, Evren, Mathews, Katherine D, Darbro, Benjamin W, Amor, David J, Walsh, Maie, Sznajer, Yves, Weiß, Luisa, Weidensee, Sabine, Chitayat, David, Shannon, Patrick, Bermejo-Sánchez, Eva, Riaño-Galán, Isolina, Hayes, Ian, Poke, Gemma, Rooryck, Caroline, Pennamen, Perrine, Khung-Savatovsky, Suonavy, Toutain, Annick, Vuillaume, Marie-Laure, Ghaderi-Sohi, Siavash, Kariminejad, Mohamad H, Weinert, Sönke, Sticht, Heinrich, Zenker, Martin, and Schanze, Denny
Abstract: Serine biosynthesis disorders comprise a spectrum of very rare autosomal recessive inborn errors of metabolism with wide phenotypic variability. Neu-Laxova syndrome represents the most severe expression and is characterized by multiple congenital anomalies and pre- or perinatal lethality. Here, we present the mutation spectrum and a detailed phenotypic analysis in 15 unrelated families with severe types of serine biosynthesis disorders. We identified likely disease-causing variants in the PHGDH and PSAT1 genes, several of which have not been reported previously. Phenotype analysis and a comprehensive review of the literature corroborates the evidence that serine biosynthesis disorders represent a continuum with varying degrees of phenotypic expression and suggest that even gradual differences at the severe end of the spectrum may be correlated with particular genotypes. We postulate that the individual residual enzyme activity of mutant proteins is the major determinant of the phenotypic variability, but further functional studies are needed to explore effects at the enzyme protein level.
Published: 2020

27. Microdeletion of the entire IRF6 gene in a Subsaharian African's family with Van der Woude syndrome.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de stomatologie et de chirurgie maxillo-faciale, Mbuyi-Musanzayi, Sébastien, Kasamba, Eric I, Revencu, Nicole, Lukusa, Prosper T, Kalenga, Prosper M, Tshilombo, François K, Reychler, Hervé, Devriendt, Koenraad, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de stomatologie et de chirurgie maxillo-faciale, Mbuyi-Musanzayi, Sébastien, Kasamba, Eric I, Revencu, Nicole, Lukusa, Prosper T, Kalenga, Prosper M, Tshilombo, François K, Reychler, Hervé, and Devriendt, Koenraad
Abstract: Microdeletion of the entire interferon regulatory factory 6 (IRF 6) gene is a rare cause of Van der Woude syndrome (VDW) with only few cases reported in medical literature. Its occurrence in multiple affected members of a family is exceptional. The aim of this presentation was to describe a Central African family with typical VDW phenotype carrying an IRF6 gene deletion. Here we reported phenotype features of members of a Central African family with VDW syndrome consisting of labioalveolar cleft, depressions of the lower lip with labial fistulae (lip pits), submucosal clefts and cleft palate. Mutation analysis by means of multiplex ligation-dependent probe amplification and chromosomal microarray revealed a 374.070 kb, deletion encompassing the entire IRF6 gene in four affected family members. Microdeletion of the entire IRF6 gene causes the classical VDW syndrome phenotype.
Published: 2020

28. Prenatally detected copy number variants in a national cohort: A postnatal follow-up study.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Muys, Joke, Jacquemyn, Yves, Blaumeiser, Bettina, Bourlard, Laura, Brison, Nathalie, Bulk, Saskia, Chiarappa, Patrizia, De Leener, Anne, De Rademaeker, Marjan, Désir, Julie, Destrée, Anne, Devriendt, Koenraad, Dheedene, Annelies, Duquenne, Armelle, Fieuw, Annelies, Fransen, Erik, Gatot, Jean-Stéphane, Jamar, Mauricette, Janssens, Sandra, Kerstjens, Jorien, Keymolen, Kathelijn, Lederer, Damien, Menten, Björn, Pichon, Bruno, Rombout, Sonia, Sznajer, Yves, Van Den Bogaert, Ann, Van Den Bogaert, Kris, Vermeesch, Joris, Janssens, Katrien, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Muys, Joke, Jacquemyn, Yves, Blaumeiser, Bettina, Bourlard, Laura, Brison, Nathalie, Bulk, Saskia, Chiarappa, Patrizia, De Leener, Anne, De Rademaeker, Marjan, Désir, Julie, Destrée, Anne, Devriendt, Koenraad, Dheedene, Annelies, Duquenne, Armelle, Fieuw, Annelies, Fransen, Erik, Gatot, Jean-Stéphane, Jamar, Mauricette, Janssens, Sandra, Kerstjens, Jorien, Keymolen, Kathelijn, Lederer, Damien, Menten, Björn, Pichon, Bruno, Rombout, Sonia, Sznajer, Yves, Van Den Bogaert, Ann, Van Den Bogaert, Kris, Vermeesch, Joris, and Janssens, Katrien
Abstract: OBJECTIVE: Belgian genetic centers established a database containing data on all chromosomal microarrays performed in a prenatal context. A study was initiated to evaluate postnatal development in children diagnosed prenatally with a non-benign copy number variant (CNV). METHODS: All children diagnosed with a prenatally detected non-benign CNV in a Belgian genetic center between May 2013 and February 2015 were included in the patient population. The control population consisted of children who had undergone an invasive procedure during pregnancy, with no or only benign CNVs. Child development was evaluated at 36 months using three (3) questionnaires: Ages and Stages Questionnaire Third edition, Ages and Stages Questionnaire Social-Emotional Second Edition and a general questionnaire. RESULTS: A significant difference in communication and personal-social development was detected between children with a reported susceptibility CNV and both children with an unreported susceptibility CNV and the control population. The outcome of children with a particular CNV is discussed in a case-by-case manner. CONCLUSION: Our postnatal follow-up project of children with a prenatally detected non-benign CNV is the first nationwide project of its kind. A higher number of cases for each CNV category is however needed to confirm our findings.
Published: 2020

29. Heterogeneous colonic content: A prenatal sonographic manifestation of lysinuric protein intolerance.

Author: UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de neurologie pédiatrique, Dimitriou, Christos, Saliba, Souha, Peyrassol, Xavier, Ben Abbou, Wafa, Nassogne, Marie-Cécile, Neugroschl, Carine, Wiame, Elsa, De Leener, Anne, Cassart, Marie, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de neurologie pédiatrique, Dimitriou, Christos, Saliba, Souha, Peyrassol, Xavier, Ben Abbou, Wafa, Nassogne, Marie-Cécile, Neugroschl, Carine, Wiame, Elsa, De Leener, Anne, and Cassart, Marie
Abstract: We report a fetus with heterogeneous colonic content, an isolated sonographic prenatal sign of lysinuric protein intolerance, a very rare metabolic disease. Familial genetic enquiries confirmed heterozygote mutation in the implicated gene in parents. The prenatal diagnosis led to neonatal dietary adaptation and avoided acute complications.
Published: 2020

30. Characterization of two new high-grade B-cell lymphoma cell lines with MYC and BCL2 rearrangements that are suitable for in vitro drug sensitivity studies

Author: UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de biologie hématologique, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service d'hématologie, UCL - SSS/DDUV/GECE - Génétique cellulaire, Dheur, Marie-Sophie, Poirel, Hélène, Ameye, Geneviève, Tilman, Gaëlle, Saussoy, Pascale, Defour, Jean-Philippe, Camboni, Alessandra, Van Den Neste, Eric, Coulie, Pierre, van Baren, Nicolas, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de biologie hématologique, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service d'hématologie, UCL - SSS/DDUV/GECE - Génétique cellulaire, Dheur, Marie-Sophie, Poirel, Hélène, Ameye, Geneviève, Tilman, Gaëlle, Saussoy, Pascale, Defour, Jean-Philippe, Camboni, Alessandra, Van Den Neste, Eric, Coulie, Pierre, and van Baren, Nicolas
Abstract: High-grade B-cell lymphomas with MYC and BCL2 or BCL6 rearrangements are highly aggressive B-cell lymphomas called double-hit lymphomas (HGBL-DH). They are particularly refractory to standard treatments and carry a poor prognosis. Fragments of resected tumoral lymph nodes from two HGBL-DH patients were put in culture. Continuously proliferating cells were characterized and compared with the original tumors. In both cases, the proliferating cells and the tumor displayed MYC and BCL2 rearrangements. Both cell lines (called LB5848-LYMP and LB5871-LYMP) presented a high proliferation rate and were maintained in culture for more than one year. Upon injection in immunodeficient mice, LB5848-LYMP gave rise to lymphoid tumors. In vitro treatment of these cell lines with a BCL2-inhibitory drug (ABT-199) selectively stopped their proliferation. These new cell lines represent valuable tools for studying HGBL-DH and for the in vitro testing of candidate therapies targeting HGBL-DH. LB5848-LYMP is also suitable for similar experiments in vivo.
Published: 2019

31. Molecular test algorithms for digestive tumours

Author: UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Service d'anatomie pathologique, Hébrant, Aline, Mourin, Anne, Froyen, Guy, Van der Meulen, Joni, de Man, Marc, Salgado, Roberto, Van den Eynde, Marc, D'haene, Nicky, Martens, Geert, Van Cutsem, Eric, Antoine-Poirel, Hélène, Tejpar, Sabine, Van Laethem, Jean-Luc, Geboes, Karen, Pauwels, Patrick, Dedeurwaerdere, Francesca, Maes, Brigitte, De Greve, Jacques, Vanhuysse, Jacques, Peeters, Pascal, Vanacker, Leen, Gomez-Galdon, Maria, Chintinne, Marie, Hendlisz, Alain, De Hertogh, Gert, Sagaert, Xavier, Peeters, Marc, Vannuffel, Pascal, Lefesvre, Pierre, Vermeij, Joanna, Simoens, Marc, Van den Moorter, Tom, Van Damme, Nancy, Van den Bulcke Marc, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Service d'anatomie pathologique, Hébrant, Aline, Mourin, Anne, Froyen, Guy, Van der Meulen, Joni, de Man, Marc, Salgado, Roberto, Van den Eynde, Marc, D'haene, Nicky, Martens, Geert, Van Cutsem, Eric, Antoine-Poirel, Hélène, Tejpar, Sabine, Van Laethem, Jean-Luc, Geboes, Karen, Pauwels, Patrick, Dedeurwaerdere, Francesca, Maes, Brigitte, De Greve, Jacques, Vanhuysse, Jacques, Peeters, Pascal, Vanacker, Leen, Gomez-Galdon, Maria, Chintinne, Marie, Hendlisz, Alain, De Hertogh, Gert, Sagaert, Xavier, Peeters, Marc, Vannuffel, Pascal, Lefesvre, Pierre, Vermeij, Joanna, Simoens, Marc, Van den Moorter, Tom, Van Damme, Nancy, and Van den Bulcke Marc
Abstract: The Belgian Commission of Personalized Medicine has been created to advise the federal government on all matters related to personalised medicine in oncology, including the reimbursement of molecular tests. Here, we propose the Belgian strategy for molecular testing in the digestive tumours within a scientific-based framework. For each tested biomarker, a clinical test level is attached, which is key to establish the relevance of the test and to define the reimbursement. For each digestive tumour type, the different molecular tests are represented as decision trees with its test utility, test level and a brief technical test description
Published: 2019

32. Functional classification of ATM variants in ataxia-telangiectasia patients.

Author: UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GEHU - Génétique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, Fiévet, Alice, Bellanger, Dorine, Rieunier, Guillaume, Dubois d'Enghien, Catherine, Sophie, Julia, Calvas, Patrick, Carriere, Jean-Paul, Anheim, Mathieu, Castrioto, Anna, Flabeau, Olivier, Degos, Bertrand, Ewenczyk, Claire, Mahlaoui, Nizar, Touzot, Fabien, Suarez, Felipe, Hully, Marie, Roubertie, Agathe, Aladjidi, Nathalie, Tison, François, Poirel, Hélène, Dahan, Karine, Doummar, Diane, Nougues, Marie-Christine, Ioos, Christine, Rougeot, Christelle, Masurel, Alice, Bourjault, Caroline, Ginglinger, Emmanuelle, Prieur, Fabienne, Siri, Aurélie, Bordigoni, Pierre, Nguyen, Karine, Philippe, Noel, Bellesme, Céline, Demeocq, François, Altuzarra, Cecilia, Mathieu-Dramard, Michèle, Couderc, Fanny, Dörk, Thilo, Auger, Nathalie, Parfait, Béatrice, Abidallah, Khadija, Moncoutier, Virginie, Collet, Agnès, Stoppa-Lyonnet, Dominique, Stern, Marc-Henri, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GEHU - Génétique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, Fiévet, Alice, Bellanger, Dorine, Rieunier, Guillaume, Dubois d'Enghien, Catherine, Sophie, Julia, Calvas, Patrick, Carriere, Jean-Paul, Anheim, Mathieu, Castrioto, Anna, Flabeau, Olivier, Degos, Bertrand, Ewenczyk, Claire, Mahlaoui, Nizar, Touzot, Fabien, Suarez, Felipe, Hully, Marie, Roubertie, Agathe, Aladjidi, Nathalie, Tison, François, Poirel, Hélène, Dahan, Karine, Doummar, Diane, Nougues, Marie-Christine, Ioos, Christine, Rougeot, Christelle, Masurel, Alice, Bourjault, Caroline, Ginglinger, Emmanuelle, Prieur, Fabienne, Siri, Aurélie, Bordigoni, Pierre, Nguyen, Karine, Philippe, Noel, Bellesme, Céline, Demeocq, François, Altuzarra, Cecilia, Mathieu-Dramard, Michèle, Couderc, Fanny, Dörk, Thilo, Auger, Nathalie, Parfait, Béatrice, Abidallah, Khadija, Moncoutier, Virginie, Collet, Agnès, Stoppa-Lyonnet, Dominique, and Stern, Marc-Henri
Abstract: Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
Published: 2019

33. ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Bauwens, Miriam, Garanto, Alejandro, Sangermano, Riccardo, Naessens, Sarah, Weisschuh, Nicole, De Zaeytijd, Julie, Khan, Mubeen, Sadler, Françoise, Balikova, Irina, Van Cauwenbergh, Caroline, Rosseel, Toon, Bauwens, Jim, De Leeneer, Kim, De Jaegere, Sarah, Van Laethem, Thalia, De Vries, Meindert, Carss, Keren, Arno, Gavin, Fakin, Ana, Webster, Andrew R, de Ravel de l'Argentière, Thomy J L, Sznajer, Yves, Vuylsteke, Marnik, Kohl, Susanne, Wissinger, Bernd, Cherry, Timothy, Collin, Rob W J, Cremers, Frans P M, Leroy, Bart P, De Baere, Elfride, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Bauwens, Miriam, Garanto, Alejandro, Sangermano, Riccardo, Naessens, Sarah, Weisschuh, Nicole, De Zaeytijd, Julie, Khan, Mubeen, Sadler, Françoise, Balikova, Irina, Van Cauwenbergh, Caroline, Rosseel, Toon, Bauwens, Jim, De Leeneer, Kim, De Jaegere, Sarah, Van Laethem, Thalia, De Vries, Meindert, Carss, Keren, Arno, Gavin, Fakin, Ana, Webster, Andrew R, de Ravel de l'Argentière, Thomy J L, Sznajer, Yves, Vuylsteke, Marnik, Kohl, Susanne, Wissinger, Bernd, Cherry, Timothy, Collin, Rob W J, Cremers, Frans P M, Leroy, Bart P, and De Baere, Elfride
Abstract: PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.
Published: 2019

34. Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service

Author: UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Westra, Dineke, Schouten, Meyke I., Stunnenberg, Bas C., Kusters, Benno, Saris, Christiaan G.J., Erasmus, Corrie E., van Engelen, Baziel G., Bulk, Saskia, Verschuuren-Bemelmans, Corien C., Gerkes, E.H., de Geus, Christa, van der Zwaag, P.A., Chan, Sophelia, Chung, Brian, Barge-Schaapveld, Daniela Q.C.M., Kriek, Marjolein, Sznajer, Yves, van Spaendonck-Zwarts, Karin, van der Kooi, Anneke J., Krause, Amanda, Schönewolf-Greulich, Bitten, de Die-Smulders, Christine, Sallevelt, Suzanne C.E.H., Krapels, Ingrid P.C., Rasmussen, Magnhild, Maystadt, Isabelle, Kievit, Anneke J.A., Witting, Nanna, Pennings, Maartje, Meijer, Rowdy, Gillissen, Christian, Kamsteeg, Erik-Jan, Voermans, Nicol C., UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de référence neuromusculaire, UCL - (SLuc) Service d'oto-rhino-laryngologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Westra, Dineke, Schouten, Meyke I., Stunnenberg, Bas C., Kusters, Benno, Saris, Christiaan G.J., Erasmus, Corrie E., van Engelen, Baziel G., Bulk, Saskia, Verschuuren-Bemelmans, Corien C., Gerkes, E.H., de Geus, Christa, van der Zwaag, P.A., Chan, Sophelia, Chung, Brian, Barge-Schaapveld, Daniela Q.C.M., Kriek, Marjolein, Sznajer, Yves, van Spaendonck-Zwarts, Karin, van der Kooi, Anneke J., Krause, Amanda, Schönewolf-Greulich, Bitten, de Die-Smulders, Christine, Sallevelt, Suzanne C.E.H., Krapels, Ingrid P.C., Rasmussen, Magnhild, Maystadt, Isabelle, Kievit, Anneke J.A., Witting, Nanna, Pennings, Maartje, Meijer, Rowdy, Gillissen, Christian, Kamsteeg, Erik-Jan, and Voermans, Nicol C.
Abstract: Background: Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials. Objective: To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms. Methods: Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many had previously undergone targeted gene testing without results. Results: Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6-genes (COL6A1, COL6A2 and COL6A3) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach. Conclusion: Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete t
Published: 2019

35. Age-related heterogeneity of Burkitt lymphoma: response to Mbulaiteye and Anderson.

Author: UCL - SSS/DDUV/GEHU - Génétique, UCL - (SLuc) Centre de génétique médicale UCL, Poirel, Hélène, Vikkula, Miikka, UCL - SSS/DDUV/GEHU - Génétique, UCL - (SLuc) Centre de génétique médicale UCL, Poirel, Hélène, and Vikkula, Miikka
Published: 2018

36. Phase II study of oral JAK1/JAK2 inhibitor ruxolitinib in advanced relapsed/refractory Hodgkin lymphoma.

Author: UCL - (MGD) Service d'hématologie, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de médecine nucléaire, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/DDUV/GECE - Génétique cellulaire, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, Van Den Neste, Eric, André, Marc, Gastinne, Thomas, Stamatoullas, Aspasia, Haioun, Corinne, Belhabri, Amine, Reman, Oumedaly, Casasnovas, Olivier, Guesquieres, Hervé, Verhoef, Gregor, Claessen, Marie-José, Poirel, Hélène, Copin, Marie-Christine, Dubois, Romain, Vandenberghe, Peter, Stoian, Ioanna-Andrea, Cottereau, Anne S, Bailly, Sarah, Knoops, Laurent, Morschhauser, Franck, UCL - (MGD) Service d'hématologie, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de médecine nucléaire, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/DDUV/GECE - Génétique cellulaire, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, Van Den Neste, Eric, André, Marc, Gastinne, Thomas, Stamatoullas, Aspasia, Haioun, Corinne, Belhabri, Amine, Reman, Oumedaly, Casasnovas, Olivier, Guesquieres, Hervé, Verhoef, Gregor, Claessen, Marie-José, Poirel, Hélène, Copin, Marie-Christine, Dubois, Romain, Vandenberghe, Peter, Stoian, Ioanna-Andrea, Cottereau, Anne S, Bailly, Sarah, Knoops, Laurent, and Morschhauser, Franck
Abstract: JAK2 constitutive activation/overexpression is common in classical Hodgkin lymphoma, and several cytokines stimulate Hodgkin lymphoma cells by recognizing JAK1-/JAK2-bound receptors. JAK blockade may thus be therapeutically beneficial in HL. This Phase II study assessed the safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in relapsed/refractory Hodgkin lymphoma patients. The primary objective was overall response rate according to IHP 2007 criteria. Thirty-three advanced patients (median prior lines: 5; refractory: 82%) were included; nine (27.3%) received at least 6 cycles of ruxolitinib and six (18.2%) > 6 cycles therapy. The overall response rate after 6 cycles was 3/32 (9.4%) patients, all partial responders, with transient stable disease in 11/32. Best overall response rate was 6/32 (18.8%). Rapid alleviation of B-symptoms was commonly noted. Median response duration was 7.7 months, median progression-free survival 3.5 months (95%CI: 1.9-4.6), and median overall survival 27.1 months (95%CI: 14.4-27.1). Forty adverse events were reported in 14/33 patients (42.4%); one led to treatment discontinuation; 87.5% recovered without sequelae. Twenty-five were of > Grade3. The latter consisted mostly of anemia (n=11) all considered related to ruxolitinib. Other main causes of > Grade3 adverse events included lymphopenia and infections. Of note, there was no Grade4 neutropenia or thrombocytopenia observed. Ruxolitinib shows signs of activity, though short-lived, beyond simple anti-inflammation. Its limited toxicity suggests the potential of being combined with other therapeutic modalities. ClinicalTrials.gov: NCT01877005.
Published: 2018

37. Childhood hearing loss is a key feature of CAPOS syndrome: A case report.

Author: UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de neurologie pédiatrique, UCL - (SLuc) Service d'ophtalmologie, UCL - (SLuc) Service d'oto-rhino-laryngologie, UCL - (SLuc) Centre de génétique médicale UCL, Paquay, Stéphanie, Wiame, Elsa, Deggouj, Naima, Boschi, Antonella, De Siati, Romolo Daniele, Sznajer, Yves, Nassogne, Marie-Cécile, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de neurologie pédiatrique, UCL - (SLuc) Service d'ophtalmologie, UCL - (SLuc) Service d'oto-rhino-laryngologie, UCL - (SLuc) Centre de génétique médicale UCL, Paquay, Stéphanie, Wiame, Elsa, Deggouj, Naima, Boschi, Antonella, De Siati, Romolo Daniele, Sznajer, Yves, and Nassogne, Marie-Cécile
Abstract: CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare neurological disorder, recently associated with the c.2452G > A hotspot mutation in the ATP1A3 gene, with sensorineural hearing loss as a prominent feature. We herein report on a girl who has experienced hearing loss for three years following an initial encephalitic episode when aged 15 months old. CAPOS was diagnosed only when she was six years old by targeted testing whilst she displayed optic atrophy, cerebellar signs and areflexia. CAPOS syndrome should be considered in the differential diagnosis of acquired childhood deafness, prompting clinicians to search for associated neurological features.
Published: 2018

38. Splice-site mutations in VEGFC cause loss of function and Nonne-Milroy-like primary lymphedema.

Author: UCL - SSS/DDUV/GEHU - Génétique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, Fastre, Elodie, Lanteigne, Lydia-Elizabeth, Helaers, Raphaël, Giacalone, Guido, Revencu, Nicole, Dionyssiou, Dimitris, Demiri, Efterpi, Brouillard, Pascal, Vikkula, Miikka, UCL - SSS/DDUV/GEHU - Génétique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, Fastre, Elodie, Lanteigne, Lydia-Elizabeth, Helaers, Raphaël, Giacalone, Guido, Revencu, Nicole, Dionyssiou, Dimitris, Demiri, Efterpi, Brouillard, Pascal, and Vikkula, Miikka
Abstract: Primary lymphedema (PLE) is phenotypically heterogeneous and partially explained by mutations in 28 genes.1, 2 In Nonne‐Milroy disease (OMIM 153100), PLE appears typically at birth and is autosomal dominant with incomplete penetrance. Several mutations have been discovered in VEGFR3, but only 2 in its ligand VEGFC (c.571_572insTT; p.Pro191Leufs*10 and c.628C>T; p.Arg210*; Figure 1G), causing Milroy‐like disease (OMIM 615907).3, 4 VEGFC regulates lymphangiogenesis upon proper activation by ADAMTS3 and CCBE1,5 mutations in which cause Hennekam lymphangiectasia‐lymphedema syndrome1 . [...]
Published: 2018

39. Evaluation of the correlation between KRAS mutated allele frequency and pathologist tumorous nuclei percentage assessment in colorectal cancer suggests a role for zygosity status

Author: UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, Libbrecht, Louis, Baldin, Paméla, Dekairelle, Anne-France, Mourin, Anne, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, Libbrecht, Louis, Baldin, Paméla, Dekairelle, Anne-France, and Mourin, Anne
Abstract: Evaluation of molecular tumour heterogeneity relies on the tumorous nuclei percentage (TNP) assessment by a pathologist, which has been criticised for being inaccurate and suffering from interobserver variability. Based on the 'Big Bang theory' which states that KRAS mutation in colorectal cancer is mostly homogeneous, we investigated this issue by performing a critical analysis of the correlation of the KRAS mutant allele fraction with the TNP in 99 colorectal tumour samples with a positive KRAS mutation status as determined by next-generation sequencing. Our results yield indirect evidence that the KRAS zygosity status influences the correlation between these parameters and we show that a well-trained pathologist is indeed capable of accurately assessing TNP. Our findings indicate that tumour zygosity, a feature which has largely been neglected until now, should be taken into account in future studies on (colorectal) molecular tumour heterogeneity
Published: 2018

40. De Novo Atypical Haemolytic Uremic Syndrome after Kidney Transplantation.

Author: UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de chirurgie et transplantation abdominale, UCL - (SLuc) Service de néphrologie, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, Devresse, Arnaud, de Meyer, Martine, Aydin, Selda, Dahan, Karin, Kanaan, Nada, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de chirurgie et transplantation abdominale, UCL - (SLuc) Service de néphrologie, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, Devresse, Arnaud, de Meyer, Martine, Aydin, Selda, Dahan, Karin, and Kanaan, Nada
Abstract: De novo thrombotic microangiopathy (TMA) can occur after kidney transplantation. An abnormality of the alternative pathway of complement must be suspected and searched for, even in presence of a secondary cause. We report the case of a 23-year-old female patient who was transplanted with a kidney from her mother for end-stage renal disease secondary to Hinman syndrome. Early after transplantation, she presented with 2 episodes of severe pyelonephritis, associated with acute kidney dysfunction and biological and histological features of TMA. Investigations of the alternative pathway of the complement system revealed atypical haemolytic uremic syndrome secondary to complement factor I mutation, associated with mutations in CD46 and complement factor H related protein genes. Plasma exchanges followed by eculizumab injections allowed improvement of kidney function without, however, normalization of creatinine.
Published: 2018

41. Corrigendum to 'A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy' [Neuromuscular disorders 27/11 (2017) 1043-1046].

Author: UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de neurologie, Van den Bergh, Peter, Sznajer, Yves, Van Parijs, Vinciane, van Tol, Walinka, Wevers, Ron Allan, Lefeber, Dirk J, Xu, Liwen, Lek, Monkol, MacArthur, Daniel G, Johnson, Katherine, Phillips, Lauren, Töpf, Ana, Straub, Volker, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de neurologie, Van den Bergh, Peter, Sznajer, Yves, Van Parijs, Vinciane, van Tol, Walinka, Wevers, Ron Allan, Lefeber, Dirk J, Xu, Liwen, Lek, Monkol, MacArthur, Daniel G, Johnson, Katherine, Phillips, Lauren, Töpf, Ana, and Straub, Volker
Abstract: The authors regret that in the Abstract and in the Molecular Analysis paragraphs of the above paper, the following was incorrect: “a homozygous c.131T > G (p.Leu44Pro) substitution”. This should read “a homozygous c.131T > C (p.Leu44Pro) substitution”. The authors would like to apologise for any inconvenience caused. They would like to thank Sally Heywood, Research Assistant, Human Gene Mutation Database, Institute of Medical Genetics, Cardiff University for bringing this error to their attention.
Published: 2018

42. Unmasking Familial CPX by WES and Identification of Novel Clinical Signs

Author: UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de chirurgie plastique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de pédiatrie générale, Demeer, Bénédicte, Revencu, Nicole, Helaers, Raphaël, Devauchelle, Bernard, François, Geneviève, Bayet, Bénédicte, Vikkula, Miikka, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de chirurgie plastique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de pédiatrie générale, Demeer, Bénédicte, Revencu, Nicole, Helaers, Raphaël, Devauchelle, Bernard, François, Geneviève, Bayet, Bénédicte, and Vikkula, Miikka
Abstract: Mutations in the T-Box transcription factor gene TBX22 are found in X-linked Cleft Palate with or without Ankyloglossia syndrome (CPX syndrome). In addition to X-linked inheritance, ankyloglossia, present in the majority of CPX patients, is an important diagnostic marker, but it is frequently missed or unreported, as it is a "minor" feature. Other described anomalies include cleft lip, micro and/or hypodontia, and features of CHARGE syndrome. We conducted whole exome sequencing (WES) on 22 individuals from 17 "a priori" non-syndromic cleft lip and/or cleft palate (CL/P) families. We filtered the data for heterozygous pathogenic variants within a set of predefined candidate genes. Two canonical splice-site mutations were found in TBX22. Detailed re-phenotyping of the two probands and their families unravelled orofacial features previously not associated with the CPX phenotypic spectrum: choanal atresia, Pierre-Robin sequence, and overgrowths on the posterior edge of the hard palate, on each side of the palatal midline. This study emphasizes the importance of WES analysis in familial CLP cases, combined with deep (reverse) phenotyping in "a priori" non-syndromic clefts
Published: 2018

43. Review of molecular mechanisms at distal Xq28 leading to balanced or unbalanced genomic rearrangements and their phenotypic impacts on hemophilia.

Author: UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre de génétique médicale UCL, Lannoy, Nathalie, Hermans, Cédric, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre de génétique médicale UCL, Lannoy, Nathalie, and Hermans, Cédric
Abstract: The distal Xq28 region is very gene-rich, comprising a relatively large number of low-copy repeats (LCRs) predisposing to genomic rearrangements. The best-known rearrangement at this locus is the F8 intron 22 inversion, responsible for up to 45% of severe hemophilia A (HA) cases. An additional inversion of intron 1 of F8 has more recently been described, affecting 2%-5% of patients with severe HA. These "balanced" rearrangements are mediated by intrachromosomal homologous recombination between inversely oriented LCRs located in intron 1 or 22 and other extragenic copies positioned more telomerically outside the F8 gene. The successive innovations of semi-quantitative technologies like multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array CGH) have rendered it possible to highlight a significant number of "unbalanced" rearrangements associated or not with these inversions. Some rearrangements are generated by the non-allelic homologous recombination (NAHR) pathway between directly oriented LCRs. Others are probably the result of unequal crossing-over or U-loop exchanges during female meiosis. This review sought to provide an overview of the mechanisms underlying rearrangements at the distal Xq28 locus and discuss their clinical impacts other than HA, such as risks of developing high inhibitor levels and spontaneous abortion, as well as other pathologies like cardiovascular disease or potentially X-linked intellectual disease.
Published: 2018

44. A Belgian consensus strategy to identify familial hypercholesterolaemia in the coronary care unit and its subsequent cascade screening and treatment: BEL-FaHST (The BELgium Familial Hypercholesterolaemia STrategy).

Author: UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de pathologie cardiovasculaire, UCL - (SLuc) Service de pathologies cardiovasculaires intensives, UCL - (SLuc) Service de soins intensifs, UCL - (SLuc) Service d'endocrinologie et de nutrition, UCL - (SLuc) Service de médecine interne générale, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (MGD) Service de cardiologie, Descamps, Olivier, Van Caenegem, Olivier, Hermans, Michel, Balligand, Jean-Luc, Beauloye, Christophe, Bondue, Antoine, Carlier, Stéphane, Castermans, Emilie, Chenot, Fabien, Claeys, Marc, De Block, Christophe, De Leener, Anne, De Meester, Antoine, Demeure, Fabian, De Raedt, Herbert, Desmet, Walter, Elegeert, Ivan, Guillaume, Michel, Hoffer, Etienne, Kacenelenbogen, Raymond, Lancellotti, Patrizio, Langlois, Michel, Leone, Attilio, Mertens, Ann, Paquot, Nicolas, Vanakker, Olivier, Vanoverschelde, Jean-Louis, Verhaegen, Ann, Vermeersch, Pieter, Wallemacq, Caroline, Rietzschel, Ernst, UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de pathologie cardiovasculaire, UCL - (SLuc) Service de pathologies cardiovasculaires intensives, UCL - (SLuc) Service de soins intensifs, UCL - (SLuc) Service d'endocrinologie et de nutrition, UCL - (SLuc) Service de médecine interne générale, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (MGD) Service de cardiologie, Descamps, Olivier, Van Caenegem, Olivier, Hermans, Michel, Balligand, Jean-Luc, Beauloye, Christophe, Bondue, Antoine, Carlier, Stéphane, Castermans, Emilie, Chenot, Fabien, Claeys, Marc, De Block, Christophe, De Leener, Anne, De Meester, Antoine, Demeure, Fabian, De Raedt, Herbert, Desmet, Walter, Elegeert, Ivan, Guillaume, Michel, Hoffer, Etienne, Kacenelenbogen, Raymond, Lancellotti, Patrizio, Langlois, Michel, Leone, Attilio, Mertens, Ann, Paquot, Nicolas, Vanakker, Olivier, Vanoverschelde, Jean-Louis, Verhaegen, Ann, Vermeersch, Pieter, Wallemacq, Caroline, and Rietzschel, Ernst
Abstract: BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is an autosomal dominant lipoprotein disorder characterized by significant elevation of low-density lipoprotein cholesterol (LDL-C) and markedly increased risk of premature cardiovascular disease (CVD). Because of the very high coronary artery disease risk associated with this condition, the prevalence of FH among patients admitted for CVD outmatches many times the prevalence in the general population. Awareness of this disease is crucial for recognizing FH in the aftermath of a hospitalization of a patient with CVD, and also represents a unique opportunity to identify relatives of the index patient, who are unaware they have FH. This article aims to describe a feasible strategy to facilitate the detection and management of FH among patients hospitalized for CVD. METHODS: A multidisciplinary national panel of lipidologists, cardiologists, endocrinologists and cardio-geneticists developed a three-step diagnostic algorithm, each step including three key aspects of diagnosis, treatment and family care. RESULTS: A sequence of tasks was generated, starting with the process of suspecting FH amongst affected patients admitted for CVD, treating them to LDL-C target, finally culminating in extensive cascade-screening for FH in their family. Conceptually, the pathway is broken down into 3 phases to provide the treating physicians with a time-efficient chain of priorities. CONCLUSIONS: We emphasize the need for optimal collaboration between the various actors, starting with a "vigilant doctor" who actively develops the capability or framework to recognize potential FH patients, continuing with an "FH specialist", and finally involving the patient himself as "FH ambassador" to approach his/her family and facilitate cascade screening and subsequent treatment of relatives.
Published: 2018

45. Case Reports in Oncological Medicine Myoepithelioma: A New Rearrangement Involving the Locus in a Case of Multiple Bone and Soft Tissue Lesions.

Author: UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service d'orthopédie et de traumatologie de l'appareil locomoteur, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - (SLuc) Service de radiologie, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/IREC/MORF - Pôle de Morphologie, Pairet, Géraldine, Tilman, Gaëlle, Sciot, Rafaël, Schubert, Thomas, Perlepe, Vasiliki, Poirel, Hélène A, Galant, Christine, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service d'orthopédie et de traumatologie de l'appareil locomoteur, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - (SLuc) Service de radiologie, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/IREC/MORF - Pôle de Morphologie, Pairet, Géraldine, Tilman, Gaëlle, Sciot, Rafaël, Schubert, Thomas, Perlepe, Vasiliki, Poirel, Hélène A, and Galant, Christine
Abstract: We report a case of multiple myoepithelioma with synchronous bone and soft tissue tumors, associated with a new genomic alteration of the locus. The lesions occurred in the foot by presenting one lump in the plantar soft tissue, and three lesions were detected in the calcaneus and in the navicular bone. All tumors showed the double immunophenotype of epithelial markers and S100 protein expression. No rearrangement of the and loci was detected as reported in myoepitheliomas. However, molecular karyotyping detected an unbalanced rearrangement of the locus, not involving the locus, which is the most frequent translocation partner observed in benign mesenchymal tumors such as lipomas (of soft tissue as well as parosteal) and pulmonary chondroid hamartoma.
Published: 2018

46. Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling

Author: UCL - (SLuc) Centre de génétique médicale UCL, Revencu, Nicole, Manchester dysmorphology conference, UCL - (SLuc) Centre de génétique médicale UCL, Revencu, Nicole, and Manchester dysmorphology conference
Published: 2018

47. Angiosarcoma arising from congenital primary lymphedema.

Author: UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de radiologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service de chirurgie plastique, UCL - (SLuc) Service de dermatologie, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique, UCL - (SLuc) Centre de malformations vasculaires congénitales, Janssens, Pauline, Dekeuleneer, Valérie, Van Damme, An, Brouillard, Pascal, Revencu, Nicole, Clapuyt, Philippe, Ferreira, Ingrid, Ballieux, Fanny, Vikkula, Miikka, Marot, Liliane, Baeck, Marie, Boon, Laurence M, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/IREC/IMAG - Pôle d'imagerie médicale, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de radiologie, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service de chirurgie plastique, UCL - (SLuc) Service de dermatologie, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique, UCL - (SLuc) Centre de malformations vasculaires congénitales, Janssens, Pauline, Dekeuleneer, Valérie, Van Damme, An, Brouillard, Pascal, Revencu, Nicole, Clapuyt, Philippe, Ferreira, Ingrid, Ballieux, Fanny, Vikkula, Miikka, Marot, Liliane, Baeck, Marie, and Boon, Laurence M
Abstract: We herein report the case of a 3-year-old girl with atypical congenital right upper limb lymphedema who developed an angiosarcoma. Only a few cases have been reported following congenital form of lymphedema and only 4 in such a young child. We also summarize all cases of angiosarcoma associated with congenital lymphedema reported in the literature.
Published: 2018

48. Identification of a new exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.

Author: UCL - (SLuc) Centre de génétique médicale UCL, Lenglet, Marion, Robriquet, Florence, Schwarz, Klaus, Camps, Carme, Couturier, Anne, Hoogewijs, David, Buffet, Alexandre, Knight, Samantha J L, Gad, Sophie, Couvé, Sophie, Chesnel, Franck, Pacault, Mathilde, Lindenbaum, Pierre, Job, Sylvie, Dumont, Solenne, Besnard, Thomas, Cornec, Marine, Dreau, Helene, Pentony, Melissa, Kvikstad, Erika, Deveaux, Sophie, Burnichon, Nelly, Ferlicot, Sophie, Vilaine, Mathias, Mazzella, Jean-Michaël, Airaud, Fabrice, Garrec, Céline, Heidet, Laurence, Irtan, Sabine, Mantadakis, Elpis, Bouchireb, Karim, Debatin, Klaus-Michael, Redon, Richard, Bezieau, Stéphane, Bressac-de Paillerets, Brigitte, Teh, Bin Tean, Girodon, François, Randi, Maria-Luigia, Putti, Maria Caterina, Bours, Vincent, Van Wijk, Richard, Göthert, Joachim R, Kattamis, Antonis, Janin, Nicolas, Bento, Celeste, Taylor, Jenny C, Arlot-Bonnemains, Yannick, Richard, Stéphane, Gimenez-Roqueplo, Anne-Paule, Cario, Holger, Gardie, Betty, UCL - (SLuc) Centre de génétique médicale UCL, Lenglet, Marion, Robriquet, Florence, Schwarz, Klaus, Camps, Carme, Couturier, Anne, Hoogewijs, David, Buffet, Alexandre, Knight, Samantha J L, Gad, Sophie, Couvé, Sophie, Chesnel, Franck, Pacault, Mathilde, Lindenbaum, Pierre, Job, Sylvie, Dumont, Solenne, Besnard, Thomas, Cornec, Marine, Dreau, Helene, Pentony, Melissa, Kvikstad, Erika, Deveaux, Sophie, Burnichon, Nelly, Ferlicot, Sophie, Vilaine, Mathias, Mazzella, Jean-Michaël, Airaud, Fabrice, Garrec, Céline, Heidet, Laurence, Irtan, Sabine, Mantadakis, Elpis, Bouchireb, Karim, Debatin, Klaus-Michael, Redon, Richard, Bezieau, Stéphane, Bressac-de Paillerets, Brigitte, Teh, Bin Tean, Girodon, François, Randi, Maria-Luigia, Putti, Maria Caterina, Bours, Vincent, Van Wijk, Richard, Göthert, Joachim R, Kattamis, Antonis, Janin, Nicolas, Bento, Celeste, Taylor, Jenny C, Arlot-Bonnemains, Yannick, Richard, Stéphane, Gimenez-Roqueplo, Anne-Paule, Cario, Holger, and Gardie, Betty
Abstract: Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau () gene. Since this discovery, additional mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' in addition to a mutation in coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other exons. In this study, we show that the mutations induced a dysregulation of splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new alterations and reveals a novel complex splicing regulation of the gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.
Published: 2018

49. Autosomal recessive primary microcephaly due to ASPM mutations: An update

Author: UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Létard, Pascaline, Drunat, Séverine, Vial, Yoann, Duerinckx, Sarah, Ernault, Anais, Amram, Daniel, Arpin, Stéphanie, Bertoli, Marta, Busa, Tiffany, Ceulemans, Berten, Desir, Julie, Doco-Fenzy, Martine, Elalaoui, Siham Chafai, Devriendt, Koenraad, Faivre, Laurence, Francannet, Christine, Geneviève, David, Gérard, Marion, Gitiaux, Cyril, Julia, Sophie, Lebon, Sébastien, Lubala, Toni, Mathieu-Dramard, Michèle, Maurey, Hélène, Metreau, Julia, Nasserereddine, Sanaa, Nizon, Mathilde, Pierquin, Geneviève, Pouvreau, Nathalie, Rivier-Ringenbach, Clothilde, Rossi, Massimiliano, Schaefer, Elise, Sefiani, Abdelaziz, Sigaudy, Sabine, Sznajer, Yves, Tunca, Yusuf, Guilmin Crepon, Sophie, Alberti, Corinne, Elmaleh-Bergès, Monique, Benzacken, Brigitte, Wollnick, Bernd, Woods, C. Geoffrey, Rauch, Anita, Abramowicz, Marc, El Ghouzzi, Vincent, Gressens, Pierre, Verloes, Alain, Passemard, Sandrine, UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Létard, Pascaline, Drunat, Séverine, Vial, Yoann, Duerinckx, Sarah, Ernault, Anais, Amram, Daniel, Arpin, Stéphanie, Bertoli, Marta, Busa, Tiffany, Ceulemans, Berten, Desir, Julie, Doco-Fenzy, Martine, Elalaoui, Siham Chafai, Devriendt, Koenraad, Faivre, Laurence, Francannet, Christine, Geneviève, David, Gérard, Marion, Gitiaux, Cyril, Julia, Sophie, Lebon, Sébastien, Lubala, Toni, Mathieu-Dramard, Michèle, Maurey, Hélène, Metreau, Julia, Nasserereddine, Sanaa, Nizon, Mathilde, Pierquin, Geneviève, Pouvreau, Nathalie, Rivier-Ringenbach, Clothilde, Rossi, Massimiliano, Schaefer, Elise, Sefiani, Abdelaziz, Sigaudy, Sabine, Sznajer, Yves, Tunca, Yusuf, Guilmin Crepon, Sophie, Alberti, Corinne, Elmaleh-Bergès, Monique, Benzacken, Brigitte, Wollnick, Bernd, Woods, C. Geoffrey, Rauch, Anita, Abramowicz, Marc, El Ghouzzi, Vincent, Gressens, Pierre, Verloes, Alain, and Passemard, Sandrine
Abstract: Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.
Published: 2018

50. CHARGE syndrome: a recurrent hotspot of mutations in CHD7 IVS25 analyzed by bioinformatic tools and minigene assays

Author: UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Legendre, Marine, Rodriguez - Ballesteros, Montserrat, Rossi, Massimiliano, Abadie, Véronique, Amiel, Jeanne, Revencu, Nicole, Blanchet, Patricia, Brioude, Frédéric, Delrue, Marie-Ange, Doubaj, Yassamine, Sefiani, Abdelaziz, Francannet, Christine, Holder-Espinasse, Muriel, Jouk, Pierre-Simon, Julia, Sophie, Melki, Judith, Mur, Sébastien, Naudion, Sophie, Fabre-Teste, Jennifer, Busa, Tiffany, Stamm, Stephen, Lyonnet, Stanislas, Attie-Bitach, Tania, Kitzis, Alain, Gilbert-Dussardier, Brigitte, Bilan, Frédéric, UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Legendre, Marine, Rodriguez - Ballesteros, Montserrat, Rossi, Massimiliano, Abadie, Véronique, Amiel, Jeanne, Revencu, Nicole, Blanchet, Patricia, Brioude, Frédéric, Delrue, Marie-Ange, Doubaj, Yassamine, Sefiani, Abdelaziz, Francannet, Christine, Holder-Espinasse, Muriel, Jouk, Pierre-Simon, Julia, Sophie, Melki, Judith, Mur, Sébastien, Naudion, Sophie, Fabre-Teste, Jennifer, Busa, Tiffany, Stamm, Stephen, Lyonnet, Stanislas, Attie-Bitach, Tania, Kitzis, Alain, Gilbert-Dussardier, Brigitte, and Bilan, Frédéric
Abstract: CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3' splice site, of which the existence was confirmed using pSpliceExpress, an easy-to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis.
Published: 2018

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

380 results on '"UCL - (SLuc) Centre de génétique médicale UCL"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources