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196 results on '"Holder-Espinasse, M."'

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

Author

Denomme-Pichon A. -S., Bruel A. -L., Duffourd Y., Safraou H., Thauvin-Robinet C., Tran Mau-Them F., Philippe C., Vitobello A., Jean-Marcais N., Moutton S., Thevenon J., Faivre L., Matalonga L., de Boer E., Gilissen C., Hoischen A., Kleefstra T., Pfundt R., de Vries B. B. A., Willemsen M. H., Vissers L. E. L. M., Jackson A., Banka S., Clayton-Smith J., Benetti E., Fallerini C., Renieri A., Ciolfi A., Dallapiccola B., Pizzi S., Radio F. C., Tartaglia M., Ellwanger K., Graessner H., Haack T. B., Zurek B., Havlovicova M., Macek M., Ryba L., Schwarz M., Votypka P., Lopez-Martin E., Posada M., Mencarelli M. A., Rooryck C., Trimouille A., Verloes A., Abbott K. M., Kerstjens M., Martin E. L., Maystadt I., Morleo M., Nigro V., Pinelli M., Riess O., Agathe J. -M. D. S., Santen G. W. E., Thauvin C., Torella A., Vissers L., Zguro K., Boer E. D., Cohen E., Danis D., Gao F., Horvath R., Johari M., Johanson L., Li S., Morsy H., Nelson I., Paramonov I., te Paske I. B. A. W., Robinson P., Savarese M., Steyaert W., Topf A., van der Velde J. K., Vandrovcova J., Ossowski S., Demidov G., Sturm M., Schulze-Hentrich J. M., Schule R., Xu J., Kessler C., Wayand M., Synofzik M., Wilke C., Traschutz A., Schols L., Hengel H., Lerche H., Kegele J., Heutink P., Brunner H., Scheffer H., Hoogerbrugge N., 't Hoen P. A. C., Sablauskas K., de Voer R. M., Kamsteeg E. -J., van de Warrenburg B., van Os N., Paske I. T., Janssen E., Steehouwer M., Yaldiz B., Brookes A. J., Veal C., Gibson S., Maddi V., Mehtarizadeh M., Riaz U., Warren G., Dizjikan F. Y., Shorter T., Straub V., Bettolo C. M., Manera J. D., Hambleton S., Engelhardt K., Alexander E., Peyron C., Pelissier A., Beltran S., Gut I. G., Laurie S., Piscia D., Papakonstantinou A., Bullich G., Corvo A., Fernandez-Callejo M., Hernandez C., Pico D., Lochmuller H., Gumus G., Bros-Facer V., Rath A., Hanauer M., Lagorce D., Hongnat O., Chahdil M., Lebreton E., Stevanin G., Durr A., Davoine C. -S., Guillot-Noel L., Heinzmann A., Coarelli G., Bonne G., Evangelista T., Allamand V., Ben Yaou R., Metay C., Eymard B., Atalaia A., Stojkovic T., Turnovec M., Thomasova D., Kremlikova R. P., Frankova V., Liskova P., Dolezalova P., Parkinson H., Keane T., Freeberg M., Thomas C., Spalding D., Robert G., Costa A., Patch C., Hanna M., Houlden H., Reilly M., Efthymiou S., Cali E., Magrinelli F., Sisodiya S. M., Rohrer J., Muntoni F., Zaharieva I., Sarkozy A., Timmerman V., Baets J., de Vries G., De Winter J., Beijer D., de Jonghe P., Van de Vondel L., De Ridder W., Weckhuysen S., Mutarelli M., Varavallo A., Banfi S., Musacchia F., Piluso G., Ferlini A., Selvatici R., Gualandi F., Bigoni S., Rossi R., Neri M., Aretz S., Spier I., Sommer A. K., Peters S., Oliveira C., Pelaez J. G., Matos A. R., Jose C. S., Ferreira M., Gullo I., Fernandes S., Garrido L., Ferreira P., Carneiro F., Swertz M. A., Johansson L., van der Vries G., Neerincx P. B., Ruvolo D., Kerstjens Frederikse W. S., Zonneveld-Huijssoon E., Roelofs-Prins D., van Gijn M., Kohler S., Metcalfe A., Drunat S., Heron D., Mignot C., Keren B., Lacombe D., Capella G., Valle L., Holinski-Feder E., Laner A., Steinke-Lange V., Cilio M. -R., Carpancea E., Depondt C., Lederer D., Sznajer Y., Duerinckx S., Mary S., Macaya A., Cazurro-Gutierrez A., Perez-Duenas B., Munell F., Jarava C. F., Maso L. B., Marce-Grau A., Colobran R., Hackman P., Udd B., Hemelsoet D., Dermaut B., Schuermans N., Poppe B., Verdin H., Osorio A. N., Depienne C., Roos A., Cordts I., Deschauer M., Striano P., Zara F., Riva A., Iacomino M., Uva P., Scala M., Scudieri P., Basak A. N., Claeys K., Boztug K., Haimel M., W. E G., Ruivenkamp C. A. L., Natera de Benito D., Thompson R., Polavarapu K., Grimbacher B., Zaganas I., Kokosali E., Lambros M., Evangeliou A., Spilioti M., Kapaki E., Bourbouli M., Balicza P., Molnar M. J., De la Paz M. P., Sanchez E. B., Delgado B. M., Alonso Garcia de la Rosa F. J., Schrock E., Rump A., Mei D., Vetro A., Balestrini S., Guerrini R., Chinnery P. F., Ratnaike T., Schon K., Maver A., Peterlin B., Munchau A., Lohmann K., Herzog R., Pauly M., May P., Beeson D., Cossins J., Furini S., Afenjar A., Goldenberg A., Masurel A., Phan A., Dieux-Coeslier A., Fargeot A., Guerrot A. -M., Toutain A., Molin A., Sorlin A., Putoux A., Jouret B., Laudier B., Demeer B., Doray B., Bonniaud B., Isidor B., Gilbert-Dussardier B., Leheup B., Reversade B., Paul C., Vincent-Delorme C., Neiva C., Poirsier C., Quelin C., Chiaverini C., Coubes C., Francannet C., Colson C., Desplantes C., Wells C., Goizet C., Sanlaville D., Amram D., Lehalle D., Genevieve D., Gaillard D., Zivi E., Sarrazin E., Steichen E., Schaefer E., Lacaze E., Jacquemin E., Bongers E., Kilic E., Colin E., Giuliano F., Prieur F., Laffargue F., Morice-Picard F., Petit F., Cartault F., Feillet F., Baujat G., Morin G., Diene G., Journel H., Perthus I., Lespinasse J., Alessandri J. -L., Amiel J., Martinovic J., Delanne J., Albuisson J., Lambert L., Perrin L., Ousager L. B., Van Maldergem L., Pinson L., Ruaud L., Samimi M., Bournez M., Bonnet-Dupeyron M. N., Vincent M., Jacquemont M. -L., Cordier-Alex M. -P., Gerard-Blanluet M., Willems M., Spodenkiewicz M., Doco-Fenzy M., Rossi M., Renaud M., Fradin M., Mathieu M., Holder-Espinasse M. H., Houcinat N., Hanna N., Leperrier N., Chassaing N., Philip N., Boute O., Van Kien P. K., Parent P., Bitoun P., Sarda P., Vabres P., Jouk P. -S., Touraine R., El Chehadeh S., Whalen S., Marlin S., Passemard S., Grotto S., Bellanger S. A., Blesson S., Nambot S., Naudion S., Lyonnet S., Odent S., Attie-Bitach T., Busa T., Drouin-Garraud V., Layet V., Bizaoui V., Cusin V., Capri Y., Alembik Y., Unión Europea. Comisión Europea. H2020, Unión Europea. Comisión Europea. 7 Programa Marco, Instituto de Salud Carlos III, Instituto Nacional de Bioinformatica (España), Ministry of Health (República Checa), Ministry of Education, Youth and Sports (República Checa), Denomme-Pichon, A. -S., Bruel, A. -L., Duffourd, Y., Safraou, H., Thauvin-Robinet, C., Tran Mau-Them, F., Philippe, C., Vitobello, A., Jean-Marcais, N., Moutton, S., Thevenon, J., Faivre, L., Matalonga, L., de Boer, E., Gilissen, C., Hoischen, A., Kleefstra, T., Pfundt, R., de Vries, B. B. A., Willemsen, M. H., Vissers, L. E. L. M., Jackson, A., Banka, S., Clayton-Smith, J., Benetti, E., Fallerini, C., Renieri, A., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Ellwanger, K., Graessner, H., Haack, T. B., Zurek, B., Havlovicova, M., Macek, M., Ryba, L., Schwarz, M., Votypka, P., Lopez-Martin, E., Posada, M., Mencarelli, M. A., Rooryck, C., Trimouille, A., Verloes, A., Abbott, K. M., Kerstjens, M., Martin, E. L., Maystadt, I., Morleo, M., Nigro, V., Pinelli, M., Riess, O., Agathe, J. -M. D. S., Santen, G. W. E., Thauvin, C., Torella, A., Vissers, L., Zguro, K., Boer, E. D., Cohen, E., Danis, D., Gao, F., Horvath, R., Johari, M., Johanson, L., Li, S., Morsy, H., Nelson, I., Paramonov, I., te Paske, I. B. A. W., Robinson, P., Savarese, M., Steyaert, W., Topf, A., van der Velde, J. K., Vandrovcova, J., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Schule, R., Xu, J., Kessler, C., Wayand, M., Synofzik, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., Lerche, H., Kegele, J., Heutink, P., Brunner, H., Scheffer, H., Hoogerbrugge, N., 't Hoen, P. A. C., Sablauskas, K., de Voer, R. M., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., Paske, I. T., Janssen, E., Steehouwer, M., Yaldiz, B., Brookes, A. J., Veal, C., Gibson, S., Maddi, V., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Manera, J. D., Hambleton, S., Engelhardt, K., Alexander, E., Peyron, C., Pelissier, A., Beltran, S., Gut, I. G., Laurie, S., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Fernandez-Callejo, M., Hernandez, C., Pico, D., Lochmuller, H., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Lagorce, D., Hongnat, O., Chahdil, M., Lebreton, E., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Bonne, G., Evangelista, T., Allamand, V., Ben Yaou, R., Metay, C., Eymard, B., Atalaia, A., Stojkovic, T., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Liskova, P., Dolezalova, P., Parkinson, H., Keane, T., Freeberg, M., Thomas, C., Spalding, D., Robert, G., Costa, A., Patch, C., Hanna, M., Houlden, H., Reilly, M., Efthymiou, S., Cali, E., Magrinelli, F., Sisodiya, S. M., Rohrer, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., de Vries, G., De Winter, J., Beijer, D., de Jonghe, P., Van de Vondel, L., De Ridder, W., Weckhuysen, S., Mutarelli, M., Varavallo, A., Banfi, S., Musacchia, F., Piluso, G., Ferlini, A., Selvatici, R., Gualandi, F., Bigoni, S., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Vries, G., Neerincx, P. B., Ruvolo, D., Kerstjens Frederikse, W. S., Zonneveld-Huijssoon, E., Roelofs-Prins, D., van Gijn, M., Kohler, S., Metcalfe, A., Drunat, S., Heron, D., Mignot, C., Keren, B., Lacombe, D., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Cilio, M. -R., Carpancea, E., Depondt, C., Lederer, D., Sznajer, Y., Duerinckx, S., Mary, S., Macaya, A., Cazurro-Gutierrez, A., Perez-Duenas, B., Munell, F., Jarava, C. F., Maso, L. B., Marce-Grau, A., Colobran, R., Hackman, P., Udd, B., Hemelsoet, D., Dermaut, B., Schuermans, N., Poppe, B., Verdin, H., Osorio, A. N., Depienne, C., Roos, A., Cordts, I., Deschauer, M., Striano, P., Zara, F., Riva, A., Iacomino, M., Uva, P., Scala, M., Scudieri, P., Basak, A. N., Claeys, K., Boztug, K., Haimel, M., W. E, G., Ruivenkamp, C. A. L., Natera de Benito, D., Thompson, R., Polavarapu, K., Grimbacher, B., Zaganas, I., Kokosali, E., Lambros, M., Evangeliou, A., Spilioti, M., Kapaki, E., Bourbouli, M., Balicza, P., Molnar, M. J., De la Paz, M. P., Sanchez, E. B., Delgado, B. M., Alonso Garcia de la Rosa, F. J., Schrock, E., Rump, A., Mei, D., Vetro, A., Balestrini, S., Guerrini, R., Chinnery, P. F., Ratnaike, T., Schon, K., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., May, P., Beeson, D., Cossins, J., Furini, S., Afenjar, A., Goldenberg, A., Masurel, A., Phan, A., Dieux-Coeslier, A., Fargeot, A., Guerrot, A. -M., Toutain, A., Molin, A., Sorlin, A., Putoux, A., Jouret, B., Laudier, B., Demeer, B., Doray, B., Bonniaud, B., Isidor, B., Gilbert-Dussardier, B., Leheup, B., Reversade, B., Paul, C., Vincent-Delorme, C., Neiva, C., Poirsier, C., Quelin, C., Chiaverini, C., Coubes, C., Francannet, C., Colson, C., Desplantes, C., Wells, C., Goizet, C., Sanlaville, D., Amram, D., Lehalle, D., Genevieve, D., Gaillard, D., Zivi, E., Sarrazin, E., Steichen, E., Schaefer, E., Lacaze, E., Jacquemin, E., Bongers, E., Kilic, E., Colin, E., Giuliano, F., Prieur, F., Laffargue, F., Morice-Picard, F., Petit, F., Cartault, F., Feillet, F., Baujat, G., Morin, G., Diene, G., Journel, H., Perthus, I., Lespinasse, J., Alessandri, J. -L., Amiel, J., Martinovic, J., Delanne, J., Albuisson, J., Lambert, L., Perrin, L., Ousager, L. B., Van Maldergem, L., Pinson, L., Ruaud, L., Samimi, M., Bournez, M., Bonnet-Dupeyron, M. N., Vincent, M., Jacquemont, M. -L., Cordier-Alex, M. -P., Gerard-Blanluet, M., Willems, M., Spodenkiewicz, M., Doco-Fenzy, M., Rossi, M., Renaud, M., Fradin, M., Mathieu, M., Holder-Espinasse, M. H., Houcinat, N., Hanna, N., Leperrier, N., Chassaing, N., Philip, N., Boute, O., Van Kien, P. K., Parent, P., Bitoun, P., Sarda, P., Vabres, P., Jouk, P. -S., Touraine, R., El Chehadeh, S., Whalen, S., Marlin, S., Passemard, S., Grotto, S., Bellanger, S. A., Blesson, S., Nambot, S., Naudion, S., Lyonnet, S., Odent, S., Attie-Bitach, T., Busa, T., Drouin-Garraud, V., Layet, V., Bizaoui, V., Cusin, V., Capri, Y., Alembik, Y., and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Exome reanalysis, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Developmental disorder, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology and Life Sciences, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], ClinVar, Rare diseases, All institutes and research themes of the Radboud University Medical Center, Medicine and Health Sciences, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Multidisciplinary, general & others [D99] [Human health sciences], Exome reanalysi, Genetics (clinical)
Abstract

Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform, which received funding from the EU projects RD-Connect, Solve-RD, and European Joint Programme on Rare Diseases (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática), and ELIXIR Implementation Studies. The collaborations in this study were facilitated by the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies, one of the 24 European Reference Networks approved by the European Reference Network Board of Member States, cofunded by the European Commission. This project was supported by the Czech Ministry of Health (number 00064203) and by the Czech Ministry of Education, Youth and Sports (number - LM2018132) to M.M. Sí

Published
2023

2. The phenotypic continuum of ATPLA3-related disorders

Author

Vezyroglou, A, Akilapa, R, Barwick, K, Koene, S, Brownstein, CA, Holder-Espinasse, M, Fry, AE, Nemeth, AH, Tofaris, GK, Hay, E, Hughes, I, Mansour, S, Mordekar, SR, Splitt, M, Turnpenny, PD, Demetriou, D, Koopmann, TT, Ruivenkamp, CAL, Agrawal, PB, Carr, L, Clowes, V, Ghali, N, Holder, SE, Radley, J, Male, A, Sisodiya, SM, Kurian, MA, Cross, JH, and Balasubramanian, M

Abstract

Background and Objectives ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process. Methods Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term “ATP1A3” from 2004 to 2021. Results Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2–3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint. Discussion Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

Published
2022

3. Correction: A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome (Genetics in Medicine, (2020), 22, 5, (867-877), 10.1038/s41436-019-0743-3)

Author

Cuvertino S., Hartill V., Colyer A., Garner T., Nair N., Al-Gazali L., Canham N., Faundes V., Flinter F., Hertecant J., Holder-Espinasse M., Jackson B., Lynch S. A., Nadat F., Narasimhan V. M., Peckham M., Sellers R., Seri M., Montanari F., Southgate L., Squeo G. M., Trembath R., van Heel D., Venuto S., Weisberg D., Stals K., Ellard S., Barton A., Kimber S. J., Sheridan E., Merla G., Stevens A., Johnson C. A., Banka S., Cuvertino, S., Hartill, V., Colyer, A., Garner, T., Nair, N., Al-Gazali, L., Canham, N., Faundes, V., Flinter, F., Hertecant, J., Holder-Espinasse, M., Jackson, B., Lynch, S. A., Nadat, F., Narasimhan, V. M., Peckham, M., Sellers, R., Seri, M., Montanari, F., Southgate, L., Squeo, G. M., Trembath, R., van Heel, D., Venuto, S., Weisberg, D., Stals, K., Ellard, S., Barton, A., Kimber, S. J., Sheridan, E., Merla, G., Stevens, A., Johnson, C. A., and Banka, S.

Abstract

Correction to: Genetics in Medicine 22:2020 https://doi.org/10.1038/s41436-019-0743-3 published online 17 January 2020. An incorrect reference was cited in the fourth sentence of the Results section. The correct citation should have been Al-Gazali LI, Hamid Z, Hertecant J et al. An autosomal recessive syndrome of choanal atresia, hypothelia/athelia and thyroid gland anomalies overlapping Bamforth syndrome, ANOTHER syndrome and methimazole embryopathy. Clin Dysmorphol 2002;2:79–85. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2020

5. Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund–Thomson/Baller-Gerold syndromes

Author

Piard, J., Aral, B., Vabres, P., Holder-Espinasse, M., Mégarbané, A., Gauthier, S., Capra, V., Pierquin, G., Callier, P., Baumann, C., Pasquier, L., Baujat, G., Martorell, L., Rodriguez, A., Brady, A. F., Boralevi, F., González-Enseñat, M. A., Rio, M., Bodemer, C., Philip, N., Cordier, M.-P., Goldenberg, A., Demeer, B., Wright, M., Blair, E., Puzenat, E., Parent, P., Sznajer, Y., Francannet, C., DiDonato, N., Boute, O., Barlogis, V., Moldovan, O., Bessis, D., Coubes, C., Tardieu, M., Cormier-Daire, V., Sousa, A. B., Franques, J., Toutain, A., Tajir, M., Elalaoui, S. C., Geneviève, D., Thevenon, J., Courcet, J.-B., Rivière, J.-B., Collet, C., Gigot, N., Faivre, L., and Thauvin-Robinet, C.

Published
2015
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6. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia

Author

Chassaing, N., Causse, A., Vigouroux, A., Delahaye, A., Alessandri, J.-L., Boespflug-Tanguy, O., Boute-Benejean, O., Dollfus, H., Duban-Bedu, B., Gilbert-Dussardier, B., Giuliano, F., Gonzales, M., Holder-Espinasse, M., Isidor, B., Jacquemont, M.-L., Lacombe, D., Martin-Coignard, D., Mathieu-Dramard, M., Odent, S., Picone, O., Pinson, L., Quelin, C., Sigaudy, S., Toutain, A., Thauvin-Robinet, C., Kaplan, Josseline, and Calvas, Patrick

Published
2014
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13. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author

Walters, R. G., Jacquemont, S., Valsesia, A., de Smith, A. J., Martinet, D., Andersson, J., Falchi, M., Chen, F., Andrieux, J., Lobbens, S., Delobel, B., Stutzmann, F., El-Sayed Moustafa, J. S., Chèvre, J.-C., Lecoeur, C., Vatin, V., Bouquillon, S., Buxton, J. L., Boute, O., Holder-Espinasse, M., Cuisset, J.-M., Lemaitre, M.-P., Ambresin, A.-E., Brioschi, A., Gaillard, M., Giusti, V., Fellmann, F., Ferrarini, A., Hadjikhani, N., Campion, D., Guilmatre, A., Goldenberg, A., Calmels, N., Mandel, J.-L., Le Caignec, C., David, A., Isidor, B., Cordier, M.-P., Dupuis-Girod, S., Labalme, A., Sanlaville, D., Béri-Dexheimer, M., Jonveaux, P., Leheup, B., Õunap, K., Bochukova, E. G., Henning, E., Keogh, J., Ellis, R. J., MacDermot, K. D., van Haelst, M. M., Vincent-Delorme, C., Plessis, G., Touraine, R., Philippe, A., Malan, V., Mathieu-Dramard, M., Chiesa, J., Blaumeiser, B., Kooy, R. F., Caiazzo, R., Pigeyre, M., Balkau, B., Sladek, R., Bergmann, S., Mooser, V., Waterworth, D., Reymond, A., Vollenweider, P., Waeber, G., Kurg, A., Palta, P., Esko, T., Metspalu, A., Nelis, M., Elliott, P., Hartikainen, A.-L., McCarthy, M. I., Peltonen, L., Carlsson, L., Jacobson, P., Sjöström, L., Huang, N., Hurles, M. E., OʼRahilly, S., Farooqi, I. S., Männik, K., Jarvelin, M.-R., Pattou, F., Meyre, D., Walley, A. J., Coin, L. J. M., Blakemore, A. I. F., Froguel, P., and Beckmann, J. S.

Published
2010
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14. MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations

Author

Le Meur, N, Holder-Espinasse, M, Jaillard, S, Goldenberg, A, Joriot, S, Amati-Bonneau, P, Guichet, A, Barth, M, Charollais, A, Journel, H, Auvin, S, Boucher, C, Kerckaert, J-P, David, V, Manouvrier-Hanu, S, Saugier-Veber, P, Frébourg, T, Dubourg, C, Andrieux, J, and Bonneau, D

Published
2010
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15. Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome

Author

Seifert, W, Holder-Espinasse, M, Spranger, S, Hoeltzenbein, M, Rossier, E, Dollfus, H, Lacombe, D, Verloes, A, Chrzanowska, K H, Maegawa, G H B, Chitayat, D, Kotzot, D, Huhle, D, Meinecke, P, Albrecht, B, Mathijssen, I, Leheup, B, Raile, K, Hennies, H C, and Horn, D

Published
2006

20. Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort

Author

Meester, J.A.N., Sukalo, M., Schröder, K.C., Schanze, D., Baynam, G., Borck, G., Bramswig, N.C., Duman, D., Gilbert-Dussardier, B., Holder-Espinasse, M., Itin, P., Johnson, D.S., Joss, S., Koillinen, H., McKenzie, F., Morton, J., Nelle, H., Reardon, W., Roll, C., Salih, M.A., Savarirayan, R., Scurr, I., Splitt, M., Thompson, E., Titheradge, H., Travers, C.P., Van Maldergem, L., Whiteford, M., Wieczorek, D., Vandeweyer, G., Trembath, R., Van Laer, L., Loeys, B.L., Zenker, M., Southgate, L., Wuyts, W., Meester, J.A.N., Sukalo, M., Schröder, K.C., Schanze, D., Baynam, G., Borck, G., Bramswig, N.C., Duman, D., Gilbert-Dussardier, B., Holder-Espinasse, M., Itin, P., Johnson, D.S., Joss, S., Koillinen, H., McKenzie, F., Morton, J., Nelle, H., Reardon, W., Roll, C., Salih, M.A., Savarirayan, R., Scurr, I., Splitt, M., Thompson, E., Titheradge, H., Travers, C.P., Van Maldergem, L., Whiteford, M., Wieczorek, D., Vandeweyer, G., Trembath, R., Van Laer, L., Loeys, B.L., Zenker, M., Southgate, L., and Wuyts, W.

Abstract

Adams–Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next‐generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype–phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.

Published
2018

21. Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort

Author

Meester, JAN, Sukalo, M, Schroeder, KC, Schanze, D, Baynam, G, Borck, G, Bramswig, NC, Duman, D, Gilbert-Dussardier, B, Holder-Espinasse, M, Itin, P, Johnson, DS, Joss, S, Koillinen, H, McKenzie, F, Morton, J, Nelle, H, Reardon, W, Roll, C, Salih, MA, Savarirayan, R, Scurr, I, Splitt, M, Thompson, E, Titheradge, H, Travers, CP, Van Maldergem, L, Whiteford, M, Wieczorek, D, Vandeweyer, G, Trembath, R, Van Laer, L, Loeys, BL, Zenker, M, Southgate, L, Wuyts, W, Meester, JAN, Sukalo, M, Schroeder, KC, Schanze, D, Baynam, G, Borck, G, Bramswig, NC, Duman, D, Gilbert-Dussardier, B, Holder-Espinasse, M, Itin, P, Johnson, DS, Joss, S, Koillinen, H, McKenzie, F, Morton, J, Nelle, H, Reardon, W, Roll, C, Salih, MA, Savarirayan, R, Scurr, I, Splitt, M, Thompson, E, Titheradge, H, Travers, CP, Van Maldergem, L, Whiteford, M, Wieczorek, D, Vandeweyer, G, Trembath, R, Van Laer, L, Loeys, BL, Zenker, M, Southgate, L, and Wuyts, W

Abstract

Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.

Published
2018

22. A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype

Author

Terhal, P.A., Nievelstein, R.J., Verver, E.J., Topsakal, V., Dommelen, P. van, Hoornaert, K., Merrer, M. Le, Zankl, A., Simon, M.E., Smithson, S.F., Marcelis, C.L.M., Kerr, B., Clayton-Smith, J., Kinning, E., Mansour, S., Elmslie, F., Goodwin, L., Hout, A.H. van der, Veenstra-Knol, H.E., Herkert, J.C., Lund, A.M., Hennekam, R.C., Mégarbané, A., Lees, M.M., Wilson, L.C., Male, A., Hurst, J., Alanay, Y., Annerén, G., Betz, R.C., Bongers, E.M.H.F., Cormier-Daire, V., Dieux, A., David, A., Elting, M.W., Ende, J. van den, Green, A., Hagen, J.M. van, Hertel, N.T., Holder-Espinasse, M., Hollander, N. den, Homfray, T., Hove, H.D., Price, S., Raas-Rothschild, A., Rohrbach, M., Schroeter, B., Suri, M., Thompson, E.M., Tobias, E.S., Toutain, A., Vreeburg, M., Wakeling, E., Knoers, N.V.A.M., Coucke, P., Mortier, G.R., Terhal, P.A., Nievelstein, R.J., Verver, E.J., Topsakal, V., Dommelen, P. van, Hoornaert, K., Merrer, M. Le, Zankl, A., Simon, M.E., Smithson, S.F., Marcelis, C.L.M., Kerr, B., Clayton-Smith, J., Kinning, E., Mansour, S., Elmslie, F., Goodwin, L., Hout, A.H. van der, Veenstra-Knol, H.E., Herkert, J.C., Lund, A.M., Hennekam, R.C., Mégarbané, A., Lees, M.M., Wilson, L.C., Male, A., Hurst, J., Alanay, Y., Annerén, G., Betz, R.C., Bongers, E.M.H.F., Cormier-Daire, V., Dieux, A., David, A., Elting, M.W., Ende, J. van den, Green, A., Hagen, J.M. van, Hertel, N.T., Holder-Espinasse, M., Hollander, N. den, Homfray, T., Hove, H.D., Price, S., Raas-Rothschild, A., Rohrbach, M., Schroeter, B., Suri, M., Thompson, E.M., Tobias, E.S., Toutain, A., Vreeburg, M., Wakeling, E., Knoers, N.V.A.M., Coucke, P., and Mortier, G.R.

Abstract

Item does not contain fulltext

Published
2015

23. Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes

Author

UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, Piard, J., Aral, B., Vabres, P., Holder-Espinasse, M., Mégarbané, A., Gauthier, S., Capra, V., Pierquin, G., Callier, P., Baumann, C., Pasquier, L., Baujat, G., Martorell, L., Rodriguez, A., Brady, A.F., Boralevi, F., González-Enseñat, M.A., Rio, M., Bodemer, C., Philip, N., Cordier, M.-P., Goldenberg, A., Demeer, B., Wright, M., Blair, E., Puzenat, E., Parent, P., Sznajer, Yves, Francannet, C., Didonato, N., Boute, O., Barlogis, V., Moldovan, O., Bessis, D., Coubes, C., Tardieu, M., Cormier-Daire, V., Sousa, A.B., Franques, J., Toutain, A., Tajir, M., Elalaoui, S.C., Geneviève, D., Thevenon, J., Courcet, J.-B., Rivière, J.-B., Collet, C., Gigot, N., Faivre, L., Thauvin-Robinet, C., UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, Piard, J., Aral, B., Vabres, P., Holder-Espinasse, M., Mégarbané, A., Gauthier, S., Capra, V., Pierquin, G., Callier, P., Baumann, C., Pasquier, L., Baujat, G., Martorell, L., Rodriguez, A., Brady, A.F., Boralevi, F., González-Enseñat, M.A., Rio, M., Bodemer, C., Philip, N., Cordier, M.-P., Goldenberg, A., Demeer, B., Wright, M., Blair, E., Puzenat, E., Parent, P., Sznajer, Yves, Francannet, C., Didonato, N., Boute, O., Barlogis, V., Moldovan, O., Bessis, D., Coubes, C., Tardieu, M., Cormier-Daire, V., Sousa, A.B., Franques, J., Toutain, A., Tajir, M., Elalaoui, S.C., Geneviève, D., Thevenon, J., Courcet, J.-B., Rivière, J.-B., Collet, C., Gigot, N., Faivre, L., and Thauvin-Robinet, C.

Abstract

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Published
2015

25. Search forReCQL4mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes

Author

Piard, J., primary, Aral, B., additional, Vabres, P., additional, Holder‐Espinasse, M., additional, Mégarbané, A., additional, Gauthier, S., additional, Capra, V., additional, Pierquin, G., additional, Callier, P., additional, Baumann, C., additional, Pasquier, L., additional, Baujat, G., additional, Martorell, L., additional, Rodriguez, A., additional, Brady, A. F., additional, Boralevi, F., additional, González‐Enseñat, M. A., additional, Rio, M., additional, Bodemer, C., additional, Philip, N., additional, Cordier, M.‐P., additional, Goldenberg, A., additional, Demeer, B., additional, Wright, M., additional, Blair, E., additional, Puzenat, E., additional, Parent, P., additional, Sznajer, Y., additional, Francannet, C., additional, DiDonato, N., additional, Boute, O., additional, Barlogis, V., additional, Moldovan, O., additional, Bessis, D., additional, Coubes, C., additional, Tardieu, M., additional, Cormier‐Daire, V., additional, Sousa, A. B., additional, Franques, J., additional, Toutain, A., additional, Tajir, M., additional, Elalaoui, S. C., additional, Geneviève, D., additional, Thevenon, J., additional, Courcet, J.‐B., additional, Rivière, J.‐B., additional, Collet, C., additional, Gigot, N., additional, Faivre, L., additional, and Thauvin‐Robinet, C., additional

Published
2014
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26. Genotype-Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS2

Author

Bornholdt, D., Atkinson, T.P., Bouadjar, B., Catteau, B., Cox, H., Silva, D. De, Fischer, J., Gunasekera, C.N., Hadj-Rabia, S., Happle, R., Holder-Espinasse, M., Kaminski, E., Konig, A., Megarbane, A., Megarbane, H., Neidel, U., Oeffner, F., Oji, V., Theos, A., Traupe, H., Vahlquist, A., Bon, B.W. van, Virtanen, M., Grzeschik, K.H., Bornholdt, D., Atkinson, T.P., Bouadjar, B., Catteau, B., Cox, H., Silva, D. De, Fischer, J., Gunasekera, C.N., Hadj-Rabia, S., Happle, R., Holder-Espinasse, M., Kaminski, E., Konig, A., Megarbane, A., Megarbane, H., Neidel, U., Oeffner, F., Oji, V., Theos, A., Traupe, H., Vahlquist, A., Bon, B.W. van, Virtanen, M., and Grzeschik, K.H.

Abstract

Item does not contain fulltext, Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.

Published
2013

27. Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability

Author

Willemsen, M.H., Valles, A., Kirkels, L.A.M.H., Mastebroek, M., Olde Loohuis, N., Kos, A., Wissink, W.M., Brouwer, A.P.M. de, Nillesen, W.M., Pfundt, R., Holder-Espinasse, M., Vallee, L., Andrieux, J., Coppens-Hofman, M.C., Rensen, H., Hamel, B.C.J., Bokhoven, H. van, Aschrafi, A., Kleefstra, T., Willemsen, M.H., Valles, A., Kirkels, L.A.M.H., Mastebroek, M., Olde Loohuis, N., Kos, A., Wissink, W.M., Brouwer, A.P.M. de, Nillesen, W.M., Pfundt, R., Holder-Espinasse, M., Vallee, L., Andrieux, J., Coppens-Hofman, M.C., Rensen, H., Hamel, B.C.J., Bokhoven, H. van, Aschrafi, A., and Kleefstra, T.

Abstract

Contains fulltext : 96723.pdf (publisher's version ) (Closed access), Background MicroRNAs (miRNAs) are non-coding gene transcripts involved in post-transcriptional regulation of genes. Recent studies identified miRNAs as important regulators of learning and memory in model organisms. So far, no mutations in specific miRNA genes have been associated with impaired cognitive functions. Methods and results In three sibs and two unrelated patients with intellectual disability (ID), overlapping 1p21.3 deletions were detected by genome-wide array analysis. The shortest region of overlap included dihydropyrimidine dehydrogenase (DPYD) and microRNA 137 (MIR137). DPYD is involved in autosomal recessive dihydropyrimidine dehydrogenase deficiency. Hemizygous DPYD deletions were previously suggested to contribute to a phenotype with autism spectrum disorder and speech delay. Interestingly, the mature microRNA transcript microRNA-137 (miR-137) was recently shown to be involved in modulating neurogenesis in adult murine neuronal stem cells. Therefore, this study investigated the possible involvement of MIR137 in the 1p21.3-deletion phenotype. The patients displayed a significantly decreased expression of both precursor and mature miR-137 levels, as well as significantly increased expression of the validated downstream targets microphthalmia-associated transcription factor (MITF) and Enhancer of Zeste, Drosophila, Homologue 2 (EZH2), and the newly identified target Kruppel-like factor 4 (KLF4). The study also demonstrated significant enrichment of miR-137 at the synapses of cortical and hippocampal neurons, suggesting a role of miR-137 in regulating local synaptic protein synthesis machinery. Conclusions This study showed that dosage effects of MIR137 are associated with 1p21.3 microdeletions and may therefore contribute to the ID phenotype in patients with deletions harbouring this miRNA. A local effect at the synapse might be responsible.

Published
2011

28. IRF6 screening of syndromic and a priori non-syndromic cleft lip and palate patients : identification of a new type of minor VWS sign.

Author

UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - SSS/DDUV - Institut de Duve, UCL - (SLuc) Centre labio-palatin Albert de Coninck, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de pédiatrie générale, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de chirurgie plastique, UCL - SSS/DDUV/GEHU - Génétique, Desmyter, Laurence, Ghassibé, Michella, Revencu, Nicole, Boute, O, Lees, M, François, Geneviève, Dumoulin, Christine, Sznajer, Yves, Moncla, A, Benateau, H., Claes, K, Devriendt, Koenraad, Mathieu, M., Van Maldergem, L., Addor, M.-C., Drouin-Garraud, V, Mortier, G., Bouma, M, Dieux-Coeslier, A, Genevieve, D, Goldenberg, A, Gozu, A, Makrythanasis, P, McEntagart, U, Sanchez, A., Vilain, C., Vermeer, S, Connell, F, Verheij, J, Manouvrier, S, Pierquin, G., Odent, S, Holder-Espinasse, M, Vincent-Delorme, C, Gillerot, Y., Vanwijck, Romain, Bayet, Bénédicte, Vikkula, Miikka, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - SSS/DDUV - Institut de Duve, UCL - (SLuc) Centre labio-palatin Albert de Coninck, UCL - (SLuc) Centre de malformations vasculaires congénitales, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de pédiatrie générale, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de chirurgie plastique, UCL - SSS/DDUV/GEHU - Génétique, Desmyter, Laurence, Ghassibé, Michella, Revencu, Nicole, Boute, O, Lees, M, François, Geneviève, Dumoulin, Christine, Sznajer, Yves, Moncla, A, Benateau, H., Claes, K, Devriendt, Koenraad, Mathieu, M., Van Maldergem, L., Addor, M.-C., Drouin-Garraud, V, Mortier, G., Bouma, M, Dieux-Coeslier, A, Genevieve, D, Goldenberg, A, Gozu, A, Makrythanasis, P, McEntagart, U, Sanchez, A., Vilain, C., Vermeer, S, Connell, F, Verheij, J, Manouvrier, S, Pierquin, G., Odent, S, Holder-Espinasse, M, Vincent-Delorme, C, Gillerot, Y., Vanwijck, Romain, Bayet, Bénédicte, and Vikkula, Miikka

Abstract

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.

Published
2010

29. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author

Walters, RG, Jacquemont, S, Valsesia, A, de Smith, AJ, Martinet, D, Andersson, J, Falchi, M, Chen, F, Andrieux, J, Lobbens, S, Delobel, B, Stutzmann, F, Moustafa, JSE-S, Chevre, J-C, Lecoeur, C, Vatin, V, Bouquillon, S, Buxton, JL, Boute, O, Holder-Espinasse, M, Cuisset, J-M, Lemaitre, M-P, Ambresin, A-E, Brioschi, A, Gaillard, M, Giusti, V, Fellmann, F, Ferrarini, A, Hadjikhani, N, Campion, D, Guilmatre, A, Goldenberg, A, Calmels, N, Mandel, J-L, Le Caignec, C, David, A, Isidor, B, Cordier, M-P, Dupuis-Girod, S, Labalme, A, Sanlaville, D, Beri-Dexheimer, M, Jonveaux, P, Leheup, B, Ounap, K, Bochukova, EG, Henning, E, Keogh, J, Ellis, RJ, MacDermot, KD, van Haelst, MM, Vincent-Delorme, C, Plessis, G, Touraine, R, Philippe, A, Malan, V, Mathieu-Dramard, M, Chiesa, J, Blaumeiser, B, Kooy, RF, Caiazzo, R, Pigeyre, M, Balkau, B, Sladek, R, Bergmann, S, Mooser, V, Waterworth, D, Reymond, A, Vollenweider, P, Waeber, G, Kurg, A, Palta, P, Esko, T, Metspalu, A, Nelis, M, Elliott, P, Hartikainen, A-L, McCarthy, MI, Peltonen, L, Carlsson, L, Jacobson, P, Sjostrom, L, Huang, N, Hurles, ME, O'Rahilly, S, Farooqi, IS, Maennik, K, Jarvelin, M-R, Pattou, F, Meyre, D, Walley, AJ, Coin, LJM, Blakemore, AIF, Froguel, P, Beckmann, JS, Walters, RG, Jacquemont, S, Valsesia, A, de Smith, AJ, Martinet, D, Andersson, J, Falchi, M, Chen, F, Andrieux, J, Lobbens, S, Delobel, B, Stutzmann, F, Moustafa, JSE-S, Chevre, J-C, Lecoeur, C, Vatin, V, Bouquillon, S, Buxton, JL, Boute, O, Holder-Espinasse, M, Cuisset, J-M, Lemaitre, M-P, Ambresin, A-E, Brioschi, A, Gaillard, M, Giusti, V, Fellmann, F, Ferrarini, A, Hadjikhani, N, Campion, D, Guilmatre, A, Goldenberg, A, Calmels, N, Mandel, J-L, Le Caignec, C, David, A, Isidor, B, Cordier, M-P, Dupuis-Girod, S, Labalme, A, Sanlaville, D, Beri-Dexheimer, M, Jonveaux, P, Leheup, B, Ounap, K, Bochukova, EG, Henning, E, Keogh, J, Ellis, RJ, MacDermot, KD, van Haelst, MM, Vincent-Delorme, C, Plessis, G, Touraine, R, Philippe, A, Malan, V, Mathieu-Dramard, M, Chiesa, J, Blaumeiser, B, Kooy, RF, Caiazzo, R, Pigeyre, M, Balkau, B, Sladek, R, Bergmann, S, Mooser, V, Waterworth, D, Reymond, A, Vollenweider, P, Waeber, G, Kurg, A, Palta, P, Esko, T, Metspalu, A, Nelis, M, Elliott, P, Hartikainen, A-L, McCarthy, MI, Peltonen, L, Carlsson, L, Jacobson, P, Sjostrom, L, Huang, N, Hurles, ME, O'Rahilly, S, Farooqi, IS, Maennik, K, Jarvelin, M-R, Pattou, F, Meyre, D, Walley, AJ, Coin, LJM, Blakemore, AIF, Froguel, P, and Beckmann, JS

Abstract

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Published
2010

30. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia

Author

Chassaing, N., primary, Causse, A., additional, Vigouroux, A., additional, Delahaye, A., additional, Alessandri, J.‐L., additional, Boespflug‐Tanguy, O., additional, Boute‐Benejean, O., additional, Dollfus, H., additional, Duban‐Bedu, B., additional, Gilbert‐Dussardier, B., additional, Giuliano, F., additional, Gonzales, M., additional, Holder‐Espinasse, M., additional, Isidor, B., additional, Jacquemont, M.‐L., additional, Lacombe, D., additional, Martin‐Coignard, D., additional, Mathieu‐Dramard, M., additional, Odent, S., additional, Picone, O., additional, Pinson, L., additional, Quelin, C., additional, Sigaudy, S., additional, Toutain, A., additional, Thauvin‐Robinet, C., additional, Kaplan, Josseline, additional, and Calvas, Patrick, additional

Published
2013
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31. Nager syndrome: confirmation ofSF3B4haploinsufficiency as the major cause

Author

Petit, F., primary, Escande, F., additional, Jourdain, A.S., additional, Porchet, N., additional, Amiel, J., additional, Doray, B., additional, Delrue, M.A., additional, Flori, E., additional, Kim, C.A., additional, Marlin, S., additional, Robertson, S.P., additional, Manouvrier-Hanu, S., additional, and Holder-Espinasse, M., additional

Published
2013
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32. Split hand/foot malformation with long-bone deficiency andBHLHA9duplication: report of 13 new families

Author

Petit, F., primary, Jourdain, A.-S., additional, Andrieux, J., additional, Baujat, G., additional, Baumann, C., additional, Beneteau, C., additional, David, A., additional, Faivre, L., additional, Gaillard, D., additional, Gilbert-Dussardier, B., additional, Jouk, P.-S., additional, Le Caignec, C., additional, Loget, P., additional, Pasquier, L., additional, Porchet, N., additional, Holder-Espinasse, M., additional, Manouvrier-Hanu, S., additional, and Escande, F., additional

Published
2013
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33. Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability

Author

Willemsen, M. H., primary, Valles, A., additional, Kirkels, L. A. M. H., additional, Mastebroek, M., additional, Olde Loohuis, N., additional, Kos, A., additional, Wissink-Lindhout, W. M., additional, de Brouwer, A. P. M., additional, Nillesen, W. M., additional, Pfundt, R., additional, Holder-Espinasse, M., additional, Vallee, L., additional, Andrieux, J., additional, Coppens-Hofman, M. C., additional, Rensen, H., additional, Hamel, B. C. J., additional, van Bokhoven, H., additional, Aschrafi, A., additional, and Kleefstra, T., additional

Published
2011
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34. What can we learn from old microdeletion syndromes using array-CGH screening?

Author

Mosca-Boidron, A L, primary, Bouquillon, S, additional, Faivre, L, additional, Callier, P, additional, Andrieux, J, additional, Marle, N, additional, Bonnet, C, additional, Vincent-Delorme, C, additional, Berri, M, additional, Plessis, G, additional, Manouvrier-Hanu, S, additional, Dieux-Coeslier, A, additional, Thauvin-Robinet, C, additional, Pipiras, E, additional, Delahaye, A, additional, Payet, M, additional, Ragon, C, additional, Masurel-Paulet, A, additional, Questiaux, E, additional, Benzacken, B, additional, Jonveaux, P, additional, Mugneret, F, additional, and Holder-Espinasse, M, additional

Published
2011
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37. IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign

Author

Desmyter, L., primary, Ghassibe, M., additional, Revencu, N., additional, Boute, O., additional, Lees, M., additional, François, G., additional, Verellen-Dumoulin, C., additional, Sznajer, Y., additional, Moncla, A., additional, Benateau, H., additional, Claes, K., additional, Devriendt, K., additional, Mathieu, M., additional, Van Maldergem, L., additional, Addor, M.-C., additional, Drouin-Garraud, V., additional, Mortier, G., additional, Bouma, M., additional, Dieux-Coeslier, A., additional, Genevieve, D., additional, Goldenberg, A., additional, Gozu, A., additional, Makrythanasis, P., additional, McEntagart, M., additional, Sanchez, A., additional, Vilain, C., additional, Vermeer, S., additional, Connell, F., additional, Verheij, J., additional, Manouvrier, S., additional, Pierquin, G., additional, Odent, S., additional, Holder-Espinasse, M., additional, Vincent-Delorme, C., additional, Gillerot, Y., additional, Vanwijck, R., additional, Bayet, B., additional, and Vikkula, M., additional

Published
2010
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38. Towards a suggestive facial dysmorphism in adenylosuccinate lyase deficiency?

Author

UCL - MD/GYPE - Département de gynécologie, d'obstétrique et de pédiatrie, UCL - (SLuc) Service de neurologie pédiatrique, Holder-Espinasse, M, Marie, Sabine, Bourrouillou, G, Ceballos-Picot, I, Nassogne, Marie-Cécile, Faivre, L., Amiel, J, Munnich, A., Vincent, Marie-Françoise, Cormier-Daire, V, UCL - MD/GYPE - Département de gynécologie, d'obstétrique et de pédiatrie, UCL - (SLuc) Service de neurologie pédiatrique, Holder-Espinasse, M, Marie, Sabine, Bourrouillou, G, Ceballos-Picot, I, Nassogne, Marie-Cécile, Faivre, L., Amiel, J, Munnich, A., Vincent, Marie-Françoise, and Cormier-Daire, V

Published
2002

39. MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations

Author

Le Meur, N., primary, Holder-Espinasse, M., additional, Jaillard, S., additional, Goldenberg, A., additional, Joriot, S., additional, Amati-Bonneau, P., additional, Guichet, A., additional, Barth, M., additional, Charollais, A., additional, Journel, H., additional, Auvin, S., additional, Boucher, C., additional, Kerckaert, J.-P., additional, David, V., additional, Manouvrier-Hanu, S., additional, Saugier-Veber, P., additional, Frebourg, T., additional, Dubourg, C., additional, Andrieux, J., additional, and Bonneau, D., additional

Published
2009
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40. Société Française d’Orthopédie Pédiatrique

Author

Holder-Espinasse, M., primary, Herbaux, B., additional, Mezel, A., additional, Lacombe, D., additional, Devisme, L., additional, Boute-Bénéjean, O., additional, Dieux-Coeslier, A., additional, Escande, F., additional, and Manouvrier-Hanu, S., additional

Published
2006
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44. A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct fromKabuki syndrome

Author

Karen Stals, Sara Cuvertino, Víctor Faundes, Frances Flinter, Lihadh Al-Gazali, Santina Venuto, Vagheesh M. Narasimhan, Laura Southgate, Colin A. Johnson, Eamonn Sheridan, Nisha Nair, Anne Barton, Alice Colyer, Susan J. Kimber, Brian R. Jackson, Adam Stevens, Daniel Weisberg, Natalie Canham, Giuseppe Merla, Gabriella Maria Squeo, Richard C. Trembath, Sally Ann Lynch, Fatima Nadat, Terence Garner, Robert Sellers, Sian Ellard, Muriel Holder-Espinasse, David A. van Heel, Michelle Peckham, Francesca Montanari, Siddharth Banka, Verity L. Hartill, Marco Seri, Jozef Hertecant, Cuvertino, S., Hartill, V., Colyer, A., Garner, T., Nair, N., Al-Gazali, L., Canham, N., Faundes, V. Flinter F., Hertecant, J., Holder-Espinasse, M., Jackson, B., Lynch, Sa, Nadat, F., Narasimhan, V., Peckham, M., Sellers, R., Seri, M., Montanari, F., Southgate, L., Squeo, Gm, Trembath, R., van Heel, D., Venuto, S., Weisberg, D., Stals, K., Ellard, S., The, 100, Barton, A., Kimber, S., Sheridan, E., Merla, G, Stevens, A., Johnson, Ca, Banka, S., Cuvertino S., Hartill V., Colyer A., Garner T., Nair N., Al-Gazali L., Canham N., Faundes V., Flinter F., Hertecant J., Holder-Espinasse M., Jackson B., Lynch S.A., Nadat F., Narasimhan V.M., Peckham M., Sellers R., Seri M., Montanari F., Southgate L., Squeo G.M., Trembath R., van Heel D., Venuto S., Weisberg D., Stals K., Ellard S., Barton A., Kimber S.J., Sheridan E., Merla G., Stevens A., Johnson C.A., and Banka S.

Subjects
Genetics, 0303 health sciences, Kabuki syndrome, Hearing loss, KMT2D, Choanal atresia, Biology, intrinsically disordered region, medicine.disease, Article, Human genetics, multiple congenital anomaly, 03 medical and health sciences, Exon, 0302 clinical medicine, 030220 oncology & carcinogenesis, DNA methylation, medicine, Missense mutation, medicine.symptom, histone 3 lysine 4 methyltransferase, Haploinsufficiency, Genetics (clinical), 030304 developmental biology
Abstract

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to alpha helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.

Published
2020

45. Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis.

Author

Calder AD, Allgrove J, Höppner J, Cheung M, Alexander S, Garagnani L, Thakker R, Jüppner H, Gardella TJ, and Holder-Espinasse M

Subjects
Humans, Female, Mutation, Male, HEK293 Cells, Syndrome, Child, Receptor, Parathyroid Hormone, Type 1 genetics, Receptor, Parathyroid Hormone, Type 1 metabolism, Parathyroid Hormone blood
Abstract

We report on 2 patients of East African ancestry with the same novel homozygous variant in the parathyroid hormone receptor type 1 (PTH1R). Both patients shared skeletal features, including brachydactyly, extensive metacarpal pseudo-epiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, and deficient sacral ossification, suggestive of Eiken syndrome. Strikingly, both patients exhibited clinically manifest parathyroid hormone (PTH) resistance with hypocalcemia and elevated serum phosphate levels. These laboratory and clinical abnormalities initially suggested pseudohypoparathyroidism, which is typically associated with GNAS abnormalities. In both patients, however, a homozygous novel PTH1R variant was identified (c.710 T > A; p.IIe237Asn, p.I237N) that is located in the second transmembrane helical domain. Previously, others have reported a patient with a nearby PTH1R mutation (D241E) who presented with similar clinical features (eg, delayed bone mineralization as well as clinical PTH resistance). Functional analysis of the effects of both novel PTH1R variants (I237N- and D241E-PTH1R) in HEK293 reporter cells transfected with plasmid DNA encoding the wild-type or mutant PTH1Rs demonstrated increased basal cAMP signaling for both variants, with relative blunting of responses to both PTH and PTH-related peptide (PTHrP) ligands. The clinical presentation of PTH resistance and delayed bone mineralization combined with the functional properties of the mutant PTH1Rs suggest that this form of Eiken syndrome results from alterations in PTH1R-mediated signaling in response to both canonical ligands, PTH and PTHrP., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2024
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47. Prenatal detection of copy number variants.

Author

Wafik M, Pendlebury-Watt A, Price K, Tomlinson C, Fowler E, Chandler N, and Holder-Espinasse M

Abstract

Prenatal detection of copy number variants (CNVs) plays an important role in the diagnosis of fetal genetic abnormalities. Understanding the methods used for prenatal CNV detection and their clinical significance contributes to the implementation of advanced genetic screening techniques in prenatal care; facilitating early identification and management of genetic disorders in fetuses. Some CNVs impose significant genetic counselling challenges; especially those which are associated with uncertain clinical significance, in the context of variable penetrance and/or expressivity or when identified incidentally. This chapter focuses on the different techniques used for detecting CNVs, including Single Nucleotide Polymorphism (SNP) arrays, comparative genomic hybridization (CGH) arrays, Non-Invasive Prenatal Testing (NIPT), Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) as well as their advantages and limitations. The tools needed for the classification of CNVs and their clinical relevance are also explored, emphasising the importance of accurate interpretation for appropriate clinical management and genetic counselling., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2024
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48. Delivery of a national prenatal exome sequencing service in England: a mixed methods study exploring healthcare professionals' views and experiences.

Author

Peter M, Mellis R, McInnes-Dean H, Daniel M, Walton H, Fisher J, Leeson-Beevers K, Allen S, Baple EL, Beleza-Meireles A, Bertoli M, Campbell J, Canham N, Cilliers D, Cobben J, Eason J, Harrison V, Holder-Espinasse M, Male A, Mansour S, McEwan A, Park SM, Smith A, Stewart A, Tapon D, Vasudevan P, Williams D, Wu WH, Chitty LS, and Hill M

Abstract

Introduction: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England, requiring the coordination of care from specialist genetics, fetal medicine (FM) and laboratory services. This mixed methods study explored the experiences of professionals involved in delivering the pES service during the first 2 years of its delivery in the NHS., Methods: A survey ( n = 159) and semi-structured interviews ( n = 63) with healthcare professionals, including clinical geneticists, FM specialists, and clinical scientists (interviews only) were used to address: 1) Views on the pES service; 2) Capacity and resources involved in offering pES; 3) Awareness, knowledge, and educational needs; and 4) Ambitions and goals for the future., Results: Overall, professionals were positive about the pES service with 77% rating it as Good or Excellent. A number of benefits were reported, including the increased opportunity for receiving actionable results for parental decision-making, improving equity of access to genomic tests and fostering close relationships between FM and genetics departments. Nonetheless, there was evidence that the shift to offering pES in a clinical setting had brought some challenges, such as additional clinic time, administrative processes, perceived lack of autonomy in decision-making regarding pES eligibility and difficulty engaging with peripheral maternity units. Concerns were also raised about the lack of confidence and gaps in genomics knowledge amongst non-genetics professionals - especially midwives. However, the findings also highlighted value in both FM, obstetric and genetics professionals benefiting from further training with a focus on recognising and managing prenatally diagnosed genetic conditions., Conclusion: Healthcare professionals are enthusiastic about the benefits of pES, and through multi-collaborative working, have developed relationships that have contributed to effective communication across specialisms. Although limitations on resources and variation in knowledge about pES have impacted service delivery, professionals were hopeful that improvements to infrastructure and the upskilling of all professionals involved in the pathway would optimise the benefits of pES for both parents and professionals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Peter, Mellis, McInnes-Dean, Daniel, Walton, Fisher, Leeson-Beevers, Allen, Baple, Beleza-Meireles, Bertoli, Campbell, Canham, Cilliers, Cobben, Eason, Harrison, Holder-Espinasse, Male, Mansour, McEwan, Park, Smith, Stewart, Tapon, Vasudevan, Williams, Wu, Chitty and Hill.)

Published
2024
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49. Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase.

Author

Jones AG, Aquilino M, Tinker RJ, Duncan L, Jenkins Z, Carvill GL, DeWard SJ, Grange DK, Hajianpour MJ, Halliday BJ, Holder-Espinasse M, Horvath J, Maitz S, Nigro V, Morleo M, Paul V, Spencer C, Esterhuizen AI, Polster T, Spano A, Gómez-Lozano I, Kumar A, Poke G, Phillips JA 3rd, Underhill HR, Gimenez G, Namba T, and Robertson SP

Subjects
Animals, Humans, Mice, Brain metabolism, Glutamates metabolism, Epilepsy, Generalized genetics, Glutamate-Ammonia Ligase genetics, Glutamate-Ammonia Ligase metabolism, Glutamine genetics, Glutamine metabolism
Abstract

Glutamine synthetase (GS), encoded by GLUL, catalyzes the conversion of glutamate to glutamine. GS is pivotal for the generation of the neurotransmitters glutamate and gamma-aminobutyric acid and is the primary mechanism of ammonia detoxification in the brain. GS levels are regulated post-translationally by an N-terminal degron that enables the ubiquitin-mediated degradation of GS in a glutamine-induced manner. GS deficiency in humans is known to lead to neurological defects and death in infancy, yet how dysregulation of the degron-mediated control of GS levels might affect neurodevelopment is unknown. We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon. Using transfection-based expression systems and mass spectrometry, these variants were shown to lead to translation initiation of GS from methionine 18, downstream of the N-terminal degron motif, resulting in a protein that is stable and enzymatically competent but insensitive to negative feedback by glutamine. Analysis of human single-cell transcriptomes demonstrated that GLUL is widely expressed in neuro- and glial-progenitor cells and mature astrocytes but not in post-mitotic neurons. One individual with a start-loss GLUL variant demonstrated periventricular nodular heterotopia, a neuronal migration disorder, yet overexpression of stabilized GS in mice using in utero electroporation demonstrated no migratory deficits. These findings underline the importance of tight regulation of glutamine metabolism during neurodevelopment in humans., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

Published
2024
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50. 'Something that helped the whole picture': Experiences of parents offered rapid prenatal exome sequencing in routine clinical care in the English National Health Service.

Author

McInnes-Dean H, Mellis R, Daniel M, Walton H, Baple EL, Bertoli M, Fisher J, Gajewska-Knapik K, Holder-Espinasse M, Lafarge C, Leeson-Beevers K, McEwan A, Pandya P, Parker M, Peet S, Roberts L, Sankaran S, Smith A, Tapon D, Wu WH, Wynn SL, Chitty LS, Hill M, and Peter M

Subjects
Pregnancy, Humans, Male, Female, Exome Sequencing, England, Counseling, Qualitative Research, State Medicine, Parents psychology
Abstract

Objectives: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England. This study aimed to explore parent experiences and their information and support needs from the perspective of parents offered pES and of health professionals involved in its delivery., Methods: In this qualitative study, semi-structured interviews were conducted with 42 women and 6 male partners and 63 fetal medicine and genetic health professionals. Interviews were transcribed verbatim and analysed using thematic analysis., Results: Overall views about pES were positive and parents were grateful to be offered the test. Highlighted benefits of pES included the value of the additional information for pregnancy management and planning for future pregnancies. An anxious wait for results was common, often associated with the need to make decisions near to 24 weeks in pregnancy when there are legal restrictions for late termination. Descriptions of dealing with uncertainty were also common, even when results had been returned. Many parents described pES results as informing decision-making around whether or not to terminate pregnancy. Some professionals were concerned that a non-informative result could be overly reassuring and highlighted that careful counselling was needed to ensure parents have a good understanding of what the result means for their pregnancy. Emotional support from professionals was valued; however, some parents felt that post-test support was lacking., Conclusion: Parents and professionals welcomed the introduction of pES. Results inform parents' decision-making around the termination of pregnancy. When there are no diagnostic findings or uncertain findings from pES, personalised counselling that considers scans and other tests are crucial. Directing parents to reliable online sources of information and providing emotional support throughout could improve their experiences of care., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Published
2024
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