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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

3. An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome

Author

Choufani, S. (Sanaa), McNiven, V. (Vanda), Cytrynbaum, C. (Cheryl), Jangjoo, M. (Maryam), Adam, M. P. (Margaret P.), Bjornsson, H. T. (Hans T.), Harris, J. (Jacqueline), Dyment, D. A. (David A.), Graham, G. E. (Gail E.), Nezarati, M. M. (Marjan M.), Aul, R. B. (Ritu B.), Castiglioni, C. (Claudia), Breckpot, J. (Jeroen), Devriendt, K. (Koen), Stewart, H. (Helen), Banos-Pinero, B. (Benito), Mehta, S. (Sarju), Sandford, R. (Richard), Dunn, C. (Carolyn), Mathevet, R. (Remi), van Maldergem, L. (Lionel), Piard, J. (Juliette), Brischoux-Boucher, E. (Elise), Vitobello, A. (Antonio), Faivre, L. (Laurence), Bournez, M. (Marie), Tran-Mau, F. (Frederic), Maystadt, I. (Isabelle), Fernandez-Jaen, A. (Alberto), Alvarez, S. (Sara), Garcia-Prieto, I. D. (Irene Diez), Alkuraya, F. S. (Fowzan S.), Alsaif, H. S. (Hessa S.), Rahbeeni, Z. (Zuhair), El-Akouri, K. (Karen), Al-Mureikhi, M. (Mariam), Spillmann, R. C. (Rebecca C.), Shashi, V. (Vandana), Sanchez-Lara, P. A. (Pedro A.), Graham, J. M. (John M., Jr.), Roberts, A. (Amy), Chorin, O. (Odelia), Evrony, G. D. (Gilad D.), Kraatari-Tiri, M. (Minna), Dudding-Byth, T. (Tracy), Richardson, A. (Anamaria), Hunt, D. (David), Hamilton, L. (Laura), Dyack, S. (Sarah), Mendelsohn, B. A. (Bryce A.), Rodriguez, N. (Nicolas), Sanchez-Martinez, R. (Rosario), Tenorio-Castano, J. (Jair), Nevado, J. (Julian), Lapunzina, P. (Pablo), Tirado, P. (Pilar), Rodrigues, M. C. (Maria-Teresa Carminho Amaro), Quteineh, L. (Lina), Innes, A. M. (A. Micheil), Kline, A. D. (Antonie D.), Au, P. Y. (P. Y. Billie), Weksberg, R. (Rosanna), Choufani, S. (Sanaa), McNiven, V. (Vanda), Cytrynbaum, C. (Cheryl), Jangjoo, M. (Maryam), Adam, M. P. (Margaret P.), Bjornsson, H. T. (Hans T.), Harris, J. (Jacqueline), Dyment, D. A. (David A.), Graham, G. E. (Gail E.), Nezarati, M. M. (Marjan M.), Aul, R. B. (Ritu B.), Castiglioni, C. (Claudia), Breckpot, J. (Jeroen), Devriendt, K. (Koen), Stewart, H. (Helen), Banos-Pinero, B. (Benito), Mehta, S. (Sarju), Sandford, R. (Richard), Dunn, C. (Carolyn), Mathevet, R. (Remi), van Maldergem, L. (Lionel), Piard, J. (Juliette), Brischoux-Boucher, E. (Elise), Vitobello, A. (Antonio), Faivre, L. (Laurence), Bournez, M. (Marie), Tran-Mau, F. (Frederic), Maystadt, I. (Isabelle), Fernandez-Jaen, A. (Alberto), Alvarez, S. (Sara), Garcia-Prieto, I. D. (Irene Diez), Alkuraya, F. S. (Fowzan S.), Alsaif, H. S. (Hessa S.), Rahbeeni, Z. (Zuhair), El-Akouri, K. (Karen), Al-Mureikhi, M. (Mariam), Spillmann, R. C. (Rebecca C.), Shashi, V. (Vandana), Sanchez-Lara, P. A. (Pedro A.), Graham, J. M. (John M., Jr.), Roberts, A. (Amy), Chorin, O. (Odelia), Evrony, G. D. (Gilad D.), Kraatari-Tiri, M. (Minna), Dudding-Byth, T. (Tracy), Richardson, A. (Anamaria), Hunt, D. (David), Hamilton, L. (Laura), Dyack, S. (Sarah), Mendelsohn, B. A. (Bryce A.), Rodriguez, N. (Nicolas), Sanchez-Martinez, R. (Rosario), Tenorio-Castano, J. (Jair), Nevado, J. (Julian), Lapunzina, P. (Pablo), Tirado, P. (Pilar), Rodrigues, M. C. (Maria-Teresa Carminho Amaro), Quteineh, L. (Lina), Innes, A. M. (A. Micheil), Kline, A. D. (Antonie D.), Au, P. Y. (P. Y. Billie), and Weksberg, R. (Rosanna)

Abstract

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an “intermediate” DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations.

Published
2022

4. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Author

Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., Eichler, E.E., Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., and Eichler, E.E.

Abstract

Contains fulltext : 245103.pdf (Publisher’s version ) (Open Access), BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare va

Published
2021

6. P215 Age at menarche in girls with cystic fibrosis

Author

Tournier, A., primary, Mittaine, M., additional, Cartault, A., additional, Bournez, M., additional, Munzer, C., additional, Murris, M., additional, Vaysse, C., additional, Brémont, F., additional, Tauber, M., additional, and Pienkowski, C., additional

Published
2018
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15. Growth during puberty in cystic fibrosis: a retrospective evaluation of a French cohort.

Author

Bournez M, Bellis G, and Huet F

Abstract

OBJECTIVES: To assess the longitudinal growth pattern in a large French cohort of patients with cystic fibrosis (CF), to determine to what extent puberty contributed to final height and to explore a potential relationship between growth, nutritional status and respiratory function. METHODS: Retrospective data were drawn from the French CF registry from 1999 to 2004. Height, weight and forced expiratory volume in 1 s (FEV(1)) were recorded annually. Growth and velocity curves were compared with reference curves. RESULTS: 729 children with CF were included. In girls, height was similar to the reference population until age 11. Age at onset of puberty was the same as in reference girls. The pubertal spurt was lower than reference values and contributed less to the final adult height. In boys, the mean height was close to the reference mean until age 14 and was thereafter lower. Age at growth acceleration was similar to that in reference boys, but with an impaired peak height velocity (PHV). The final height was lower than in the general population (z score -0.73). No correlations were found between body mass index (BMI) and PHV. In girls, there was a weak but significant positive relationship between PHV and FEV(1) (r=0.17, p=0.02) CONCLUSIONS: In this cohort, children with CF had a normal age of onset of puberty and pubertal spurt, with a low PHV. Puberty contributed less to final adult height, and neither BMI nor FEV(1) had a significant effect on pubertal height gain. [ABSTRACT FROM AUTHOR]

Published
2012
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16. Penetrance, variable expressivity and monogenic neurodevelopmental disorders.

Author

de Masfrand S, Cogné B, Nizon M, Deb W, Goldenberg A, Lecoquierre F, Nicolas G, Bournez M, Vitobello A, Mau-Them FT, le Guyader G, Bilan F, Bauer P, Zweier C, Piard J, Pasquier L, Bézieau S, Gerard B, Faivre L, Saugier-Veber P, Piton A, and Isidor B

Subjects
Humans, Female, Male, Child, Child, Preschool, Adult, Adolescent, Mutation, Infant, Penetrance, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology, Pedigree
Abstract

Purpose: Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance., Method: From 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study., Results: We identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with de novo variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2 and RERE. Grandparents have been tested in 6 families, and each time the variant was confirmed de novo in the healthy carrier parent., Conclusion: Incomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Published
2024
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17. Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders.

Author

Husson T, Lecoquierre F, Nicolas G, Richard AC, Afenjar A, Audebert-Bellanger S, Badens C, Bilan F, Bizaoui V, Boland A, Bonnet-Dupeyron MN, Brischoux-Boucher E, Bonnet C, Bournez M, Boute O, Brunelle P, Caumes R, Charles P, Chassaing N, Chatron N, Cogné B, Colin E, Cormier-Daire V, Dard R, Dauriat B, Delanne J, Deleuze JF, Demurger F, Denommé-Pichon AS, Depienne C, Dieux A, Dubourg C, Edery P, El Chehadeh S, Faivre L, Fergelot P, Fradin M, Garde A, Geneviève D, Gilbert-Dussardier B, Goizet C, Goldenberg A, Gouy E, Guerrot AM, Guimier A, Harzalla I, Héron D, Isidor B, Lacombe D, Le Guillou Horn X, Keren B, Kuechler A, Lacaze E, Lavillaureix A, Lehalle D, Lesca G, Lespinasse J, Levy J, Lyonnet S, Morel G, Jean-Marçais N, Marlin S, Marsili L, Mignot C, Nambot S, Nizon M, Olaso R, Pasquier L, Perrin L, Petit F, Pingault V, Piton A, Prieur F, Putoux A, Planes M, Odent S, Quélin C, Quemener-Redon S, Rama M, Rio M, Rossi M, Schaefer E, Rondeau S, Saugier-Veber P, Smol T, Sigaudy S, Touraine R, Mau-Them FT, Trimouille A, Van Gils J, Vanlerberghe C, Vantalon V, Vera G, Vincent M, Ziegler A, Guillin O, Campion D, and Charbonnier C

Subjects
Humans, DNA Methylation, Biomarkers, Pathology, Molecular, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics
Abstract

Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 101 carriers of (likely) pathogenic variants in ten different genes, 57 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached <40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70-100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures., (© 2023. The Author(s).)

Published
2024
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18. Patient satisfaction, experience and preferences in the implementation of genetics teleconsultations in the North-eastern region of France.

Author

Lançon A, Beaudouin A, Lambert L, Baurand A, Petit E, Schaefer E, Poirsier C, Piard J, Patay L, Garde A, Bournez M, Bertolone G, Kastner C, Tempé L, El Chehadeh S, Spodenkiewick M, Lissy L, Doco-Fenzy M, Cabrol C, Trouvé C, Brischoux EB, Cloteau M, Burtin A, Renaud M, Riviere A, Thomas Q, De Souza CS, Sawka C, Racine C, Robert M, Gautier E, Delanne J, Bertaut A, Thauvin-Robinet C, Faivre L, and Nambot S

Subjects
Humans, Female, Adult, Male, Patient Satisfaction, Pandemics, Communicable Disease Control, Remote Consultation methods, COVID-19 epidemiology
Abstract

Introduction: In France, few centres per region offer genetics consultations. Consequently, each centre covers a large area, often requiring patients to take a day off to travel long distances. In certain situations, genetic counselling in particular, a physical exam is not required. In these cases, teleconsultations between medical professional and patients, at the patient's location of choice, are an interesting offer. The COVID-19 pandemic has accelerated the implementation and the use of this type of consultation. With the aim of developing teleconsultation for certain types of referrals, a study of patient satisfaction, experience and preferences has been set up in our region., Methods: 2307 patients who had a teleconsultation by phone or videoconferencing with professionals from one of five genetic centres in North-eastern France between March and December 2020 were asked by e-mail or by post to answer an online survey., Results: 20% of the patients (n = 465) responded to the survey (80% women, 55% over 40 years old). In 64% of the cases (n = 299), the teleconsultation replaced a physical consultation due to the pandemic. In 56% of cases (n = 217), the consultations were conducted by videoconference. The teleconsultation involved the disclosure of results in 56% of cases (n = 260), a first consultation in 30% of cases (n = 138), and a follow-up consultation in 14% of cases (n = 67). The satisfaction rate was 96% (n = 447), with a rating of "excellent" in 72% of responses (n = 290) and "good" in 24% of responses (n = 157). Only 22% of the patients (n = 103), particularly patients who lived near the hospital or who were older than 70 years, would have preferred a physical consultation. Half of respondents (n = 232) declared that they avoided more than 1.5 h of transport, and 69% (n = 321) avoided taking a work day off. Patients were less often accompanied by a relative than if the consultation had taken place face-to-face (43%; n = 201 vs. 61%; n = 285). There was no change in responses during or after lock-down., Conclusion: This collection of feedback and analysis of patients' preferences has validated the long-term implementation of medical genetics teleconsultations in certain circumstances and indications, for patients who prefer this approach., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Published
2023
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19. Epileptic encephalopathy as a new feature of the sudden infant death with dysgenesis of the testes syndrome caused by TSPYL1 variants.

Author

Mazel B, Mallet D, Roucher-Boulez F, Signor CB, Bournez M, Darmency V, Bourgeois V, Poe C, El Khabbaz F, Vitobello A, Philippe C, Duffourd Y, Thauvin-Robinet C, Faivre L, and Nambot S

Subjects
Male, Humans, Testis, Phenotype, Seizures, Nuclear Proteins genetics, Sudden Infant Death genetics, Epilepsy genetics, Epilepsy, Generalized
Abstract

Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is a rare autosomal recessive disorder associating developmental sex disorder (DSD) in patients with 46,XY karyotype and visceroautonomic dysfunction responsible for sudden infant death. First described in 2004, very few patients have since been reported. We describe here a new patient with SIDDT and epileptic encephalopathy (EE). We provide the phenotypic description and genetic results of a boy carrying biallelic TSPYL1 deleterious variants. We also reviewed the data of the 26 previously described patients with SIDDT. Our patient presented gonadal dysgenesis, cardio-respiratory dysfunction, and repeated seizures, leading in 1 month to severe intractable EE. He died at age 10 months of cardiorespiratory arrest. Four other reported patients from two families presented with progressive epilepsy, including one with severe EE. No similar phenotype was described in the 22 other patients and the recurrent variant p.Val242Glufs*52 appears to be more frequently associated with seizures. To note, our patient is the first case with compound heterozygous TSPYL1 variants. These findings expand the phenotypic spectrum of SIDDT by reporting progressive epilepsy and severe EE as a possible outcome. This information may help in managing patients with SIDDT., (© 2022 Wiley Periodicals LLC.)

Published
2022
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20. Consolidation of the clinical and genetic definition of a SOX4- related neurodevelopmental syndrome.

Author

Angelozzi M, Karvande A, Molin AN, Ritter AL, Leonard JMM, Savatt JM, Douglass K, Myers SM, Grippa M, Tolchin D, Zackai E, Donoghue S, Hurst ACE, Descartes M, Smith K, Velasco D, Schmanski A, Crunk A, Tokita MJ, de Lange IM, van Gassen K, Robinson H, Guegan K, Suri M, Patel C, Bournez M, Faivre L, Tran-Mau-Them F, Baker J, Fabie N, Weaver K, Shillington A, Hopkin RJ, Barge-Schaapveld DQCM, Ruivenkamp CA, Bökenkamp R, Vergano S, Seco Moro MN, Díaz de Bustamante A, Misra VK, Kennelly K, Rogers C, Friedman J, Wigby KM, Lenberg J, Graziano C, Ahrens-Nicklas RC, and Lefebvre V

Subjects
Humans, Syndrome, Phenotype, DNA, SOXC Transcription Factors genetics, Micrognathism genetics, Hand Deformities, Congenital genetics, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
Abstract

Background: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome., Methods: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes., Results: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11- related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS., Conclusion: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes., Competing Interests: Competing interests: AC and MJT are employees of GeneDx, Inc. Other authors have no competing interests., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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21. An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.

Author

Choufani S, McNiven V, Cytrynbaum C, Jangjoo M, Adam MP, Bjornsson HT, Harris J, Dyment DA, Graham GE, Nezarati MM, Aul RB, Castiglioni C, Breckpot J, Devriendt K, Stewart H, Banos-Pinero B, Mehta S, Sandford R, Dunn C, Mathevet R, van Maldergem L, Piard J, Brischoux-Boucher E, Vitobello A, Faivre L, Bournez M, Tran-Mau F, Maystadt I, Fernández-Jaén A, Alvarez S, García-Prieto ID, Alkuraya FS, Alsaif HS, Rahbeeni Z, El-Akouri K, Al-Mureikhi M, Spillmann RC, Shashi V, Sanchez-Lara PA, Graham JM Jr, Roberts A, Chorin O, Evrony GD, Kraatari-Tiri M, Dudding-Byth T, Richardson A, Hunt D, Hamilton L, Dyack S, Mendelsohn BA, Rodríguez N, Sánchez-Martínez R, Tenorio-Castaño J, Nevado J, Lapunzina P, Tirado P, Carminho Amaro Rodrigues MT, Quteineh L, Innes AM, Kline AD, Au PYB, and Weksberg R

Subjects
Abnormalities, Multiple, Chromatin, Epigenesis, Genetic, Face abnormalities, Hematologic Diseases, Heterogeneous-Nuclear Ribonucleoprotein K genetics, Humans, Phenotype, Vestibular Diseases, DNA Methylation genetics, Intellectual Disability genetics
Abstract

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations., Competing Interests: Declaration of interests H.T.B. is a consultant for Mahzi therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2022
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22. A novel mutation of PCSK1 responsible for PC1/3 deficiency in two siblings.

Author

Duclaux-Loras R, Bourgeois P, Lavrut PM, Charbit-Henrion F, Bonniaud-Blot P, Maudinas R, Bournez M, Faure M, Cerf-Bensussan N, Lachaux A, Peretti N, and Fabre A

Subjects
Child, Preschool, Diarrhea, Humans, Infant, Newborn, Mutation, Obesity, Proinsulin, Siblings, Intestinal Failure, Proprotein Convertase 1 genetics
Abstract

Proprotein convertase 1 (PCSK1, PC1/3) deficiency is an uncommon cause of neonatal malabsorptive diarrhoea associated with endocrinopathies that are due to the disrupted processing of a large number of prohormones, including proinsulin. To date, only 26 cases have been reported. Herein, we describe two siblings with typical features including severe congenital diarrhoea, central diabetes insipidus, growth hormone deficiency, and hypoadrenalism. Next generation sequencing found a homozygous missense mutation in exon 5 of PCSK1 gene, c.500A>C (p.Asp167Ala), located within the catalytic domain. Both patients presented a high level of proinsulin. In the first years of life they required parenteral nutrition and hormone replacement therapy. The patients, aged 3 and 1.5 years, experienced several infectious episodes associated with septic shocks. While the mechanism underlying intestinal failure remains poorly investigated, parenteral nutrition is essential in order to ensure normal growth in early childhood., (Copyright © 2021. Published by Elsevier Masson SAS.)

Published
2021
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23. The diagnostic rate of inherited metabolic disorders by exome sequencing in a cohort of 547 individuals with developmental disorders.

Author

Delanne J, Bruel AL, Huet F, Moutton S, Nambot S, Grisval M, Houcinat N, Kuentz P, Sorlin A, Callier P, Jean-Marcais N, Mosca-Boidron AL, Mau-Them FT, Denommé-Pichon AS, Vitobello A, Lehalle D, El Chehadeh S, Francannet C, Lebrun M, Lambert L, Jacquemont ML, Gerard-Blanluet M, Alessandri JL, Willems M, Thevenon J, Chouchane M, Darmency V, Fatus-Fauconnier C, Gay S, Bournez M, Masurel A, Leguy V, Duffourd Y, Philippe C, Feillet F, Faivre L, and Thauvin-Robinet C

Abstract

Considering that some Inherited Metabolic Disorders (IMDs) can be diagnosed in patients with no distinctive clinical features of IMDs, we aimed to evaluate the power of exome sequencing (ES) to diagnose IMDs within a cohort of 547 patients with unspecific developmental disorders (DD). IMDs were diagnosed in 12% of individuals with causative diagnosis (177/547). There are clear benefits of using ES in DD to diagnose IMD, particularly in cases where biochemical studies are unavailable., Synopsis: Exome sequencing and diagnostic rate of Inherited Metabolic Disorders in individuals with developmental disorders., Competing Interests: The authors declare no conflicts of interest., (© 2021 Published by Elsevier Inc.)

Published
2021
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24. Care management in a French cohort with Down syndrome from the AnDDI-Rares/CNSA study.

Author

Roux-Levy PH, Sanlaville D, De Freminville B, Touraine R, Masurel A, Gueneau I, Cotinaud-Ricou A, Chancenotte S, Debomy F, Minot D, Bournez M, Rousseau I, Daniel S, Gautier E, Lacombe D, Taupiac E, Odent S, Mikaty M, Manouvrier S, Ghoumid J, Geneviève D, Lehman N, Busa T, Edery CP, Cornaton J, Gallard J, Héron D, Rastel C, Thauvin-Robinet C, Verloes A, Binquet C, Faivre L, and Lejeune C

Subjects
Adolescent, Child, Child, Preschool, Education of Intellectually Disabled organization & administration, Education of Intellectually Disabled standards, Female, France, Health Services Accessibility organization & administration, Health Services Accessibility standards, Humans, Interdisciplinary Communication, Male, Neurological Rehabilitation organization & administration, Patient Care Management organization & administration, Social Support, Waiting Lists, Young Adult, Down Syndrome rehabilitation, Neurological Rehabilitation standards, Patient Care Management standards
Abstract

Down syndrome (DS) is a genetic neurodevelopmental disorder. In individuals with DS, a multidisciplinary approach to care is required to prevent multiple medical complications. The aim of this study was to describe the rehabilitation, medical care, and educational and social support provided to school-aged French DS patients with varying neuropsychological profiles. A mixed study was conducted. Quantitative data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Qualitative data were collected by semi-structured face-to-face interviews and focus groups. Ninety-five DS subjects with a mean age of 10.9 years were included. Sixty-six per cent had a moderate intellectual disability (ID) and 18.9% had a severe ID. Medical supervision was generally multidisciplinary but access to medical specialists was often difficult. In terms of education, 94% of children under the age of six were in typical classes. After the age of 15, 75% were in medico-social institutions. Analysis of multidisciplinary rehabilitation conducted in the public and private sectors revealed failure to access physiotherapy, psychomotor therapy and occupational therapy, but not speech therapy. The main barrier encountered by patients was the difficulty accessing appropriate facilities due to a lack of space and long waiting lists. In conclusion, children and adolescents with DS generally received appropriate care. Though the management of children with DS has been improved considerably, access to health facilities remains inadequate., (Copyright © 2021. Published by Elsevier Masson SAS.)

Published
2021
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25. Next-Generation Sequencing Analysis Reveals Frequent Familial Origin and Oligogenism in Congenital Hypothyroidism With Dyshormonogenesis.

Author

Oliver-Petit I, Edouard T, Jacques V, Bournez M, Cartault A, Grunenwald S, and Savagner F

Subjects
Autoantigens genetics, Dual Oxidases genetics, Female, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Iodide Peroxidase genetics, Iron-Binding Proteins genetics, Male, Receptors, Thyrotropin genetics, Symporters genetics, Congenital Hypothyroidism genetics
Abstract

Context: Congenital hypothyroidism (CH) is related to dyshormonogenesis in 15% to 40% of the world population and associated with homozygous or heterozygous variants in the main genes of the hormone synthesis pathway. Emerging diagnostic tools, such as next-generation sequencing (NGS), have been used to efficiently explore panels of genes and identify complex mechanisms of pathogenesis., Objective: We explored 19 candidate genes known to be causative for permanent or transient CH to evaluate the role of complex gene variations in CH phenotype., Patients Design and Setting: Using the NGS approach, we studied 65 newborns with thyroid dyshormonogenesis (TDH). New variants were assessed in silico for pathogenicity., Results: Among the 65 infants, 56.9% presented a variant in one or more genes of the thyroid hormone synthesis axis. We identified homozygous or compound heterozygous variants in the TG , DUOX2 , TPO , or SLC5A5 genes in 10 infants and heterozygous variants in DUOX2 , TG , TPO , and TSHR in 19 others. In seven cases, a heterozygous variant in the TG gene was the unique anomaly detected, but related to disturbed hormonal balance. Oligogenic variants were found in eight infants associated with severe CH and goiter in five of them., Conclusion: The systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter., 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 © 2021 Oliver-Petit, Edouard, Jacques, Bournez, Cartault, Grunenwald and Savagner.)

Published
2021
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26. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Author

Gillentine MA, Wang T, Hoekzema K, Rosenfeld J, Liu P, Guo H, Kim CN, De Vries BBA, Vissers LELM, Nordenskjold M, Kvarnung M, Lindstrand A, Nordgren A, Gecz J, Iascone M, Cereda A, Scatigno A, Maitz S, Zanni G, Bertini E, Zweier C, Schuhmann S, Wiesener A, Pepper M, Panjwani H, Torti E, Abid F, Anselm I, Srivastava S, Atwal P, Bacino CA, Bhat G, Cobian K, Bird LM, Friedman J, Wright MS, Callewaert B, Petit F, Mathieu S, Afenjar A, Christensen CK, White KM, Elpeleg O, Berger I, Espineli EJ, Fagerberg C, Brasch-Andersen C, Hansen LK, Feyma T, Hughes S, Thiffault I, Sullivan B, Yan S, Keller K, Keren B, Mignot C, Kooy F, Meuwissen M, Basinger A, Kukolich M, Philips M, Ortega L, Drummond-Borg M, Lauridsen M, Sorensen K, Lehman A, Lopez-Rangel E, Levy P, Lessel D, Lotze T, Madan-Khetarpal S, Sebastian J, Vento J, Vats D, Benman LM, Mckee S, Mirzaa GM, Muss C, Pappas J, Peeters H, Romano C, Elia M, Galesi O, Simon MEH, van Gassen KLI, Simpson K, Stratton R, Syed S, Thevenon J, Palafoll IV, Vitobello A, Bournez M, Faivre L, Xia K, Earl RK, Nowakowski T, Bernier RA, and Eichler EE

Subjects
Brain metabolism, DNA Copy Number Variations genetics, Gene Expression Regulation, Genetic Association Studies, Genetic Variation, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Humans, Inheritance Patterns genetics, Mutation, Missense genetics, Phenotype, RNA Processing, Post-Transcriptional genetics, Single-Cell Analysis, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoproteins genetics, Mutation genetics, Neurodevelopmental Disorders genetics
Abstract

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations., Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk., Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs., Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Published
2021
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27. Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome.

Author

Roux-Levy PH, Bournez M, Masurel A, Jean N, Chancenotte S, Bordes M, Debomy F, Minot D, Schmitt E, Vinault S, Gautier E, Lacombe D, Odent S, Mikaty M, Manouvrier S, Ghoumid J, Geneviève D, Lehman N, Philip N, Edery P, Cornaton J, Gallard J, Héron D, Rastel C, Huet F, Thauvin-Robinet C, Verloes A, Binquet C, Tauber M, Lejeune C, and Faivre L

Subjects
Adolescent, Child, Child, Preschool, Education, Special statistics & numerical data, Female, France, Hormone Replacement Therapy statistics & numerical data, Humans, Male, Prader-Willi Syndrome drug therapy, Prader-Willi Syndrome physiopathology, Young Adult, Cognition, Neurological Rehabilitation statistics & numerical data, Prader-Willi Syndrome rehabilitation, Social Support
Abstract

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision., (Copyright © 2020. Published by Elsevier Masson SAS.)

Published
2020
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28. Maternity or parental leave and breastfeeding duration: Results from the ELFE cohort.

Author

de Lauzon-Guillain B, Thierry X, Bois C, Bournez M, Davisse-Paturet C, Dufourg MN, Kersuzan C, Ksiazek E, Nicklaus S, Vicaire H, Wagner S, Lioret S, and Charles MA

Subjects
Adult, Female, France, Humans, Infant, Infant, Newborn, Longitudinal Studies, Male, Return to Work statistics & numerical data, Young Adult, Breast Feeding statistics & numerical data, Parental Leave statistics & numerical data
Abstract

Previous studies have shown a high level of noncompliance with recommendations on breastfeeding duration, especially in France. The objective was to describe the association between breastfeeding initiation and duration and the statutory duration of postnatal maternity leave, the gap between the end of legal maternity leave and the mother's return to work, and maternal working time during the first year post-partum. Analyses were based on 8,009 infants from the French nationwide ELFE cohort. We assessed the association with breastfeeding initiation by using logistic regression and, among breastfeeding women, with categories of breastfeeding duration by using multinomial logistic regression. Among primiparous women, both postponing return to work for at least 3 weeks after statutory postnatal maternity leave (as compared with returning to work at the end of the statutory period) and working less than full-time at 1 year post-partum (as compared with full-time) were related to higher prevalence of breastfeeding initiation. Among women giving birth to their first or second child, postponing the return to work until at least 15 weeks was related to a higher prevalence of long breastfeeding duration (at least 6 months) as compared with intermediate duration (3 to <6 months). Working part-time was also positively related to breastfeeding duration. Among women giving birth to their third child or more, working characteristics were less strongly related to breastfeeding duration. These results support extending maternity leave or working time arrangements to encourage initiation and longer duration of breastfeeding., (© 2019 John Wiley & Sons Ltd.)

Published
2019
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29. Frequency of Use of Added Sugar, Salt, and Fat in Infant Foods up to 10 Months in the Nationwide ELFE Cohort Study: Associated Infant Feeding and Caregiving Practices.

Author

Bournez M, Ksiazek E, Charles MA, Lioret S, Brindisi MC, de Lauzon-Guillain B, and Nicklaus S

Subjects
Breast Feeding, Cohort Studies, Data Collection, Diet, Dietary Carbohydrates analysis, Dietary Fats analysis, Female, Food Analysis, Humans, Infant, Male, Sodium Chloride, Dietary analysis, Dietary Carbohydrates administration & dosage, Dietary Fats administration & dosage, Infant Food analysis, Sodium Chloride, Dietary administration & dosage, Sugars administration & dosage
Abstract

The consumption of sugar, salt, and fat in infancy may influence later health. The objective of this study was to describe the frequency of use of added sugar, salt, and fat during the complementary feeding period and the associated infant caregiving practices. Data were obtained from a monthly questionnaire filled by parents for 10,907 infants from the French Etude Longitudinale Française depuis l'Enfance (ELFE) cohort. A score of frequency of use (SU) for added sugar, salt, and fat (oil, margarine, butter, and/or cream) was calculated from the age at complementary feeding introduction (CFI) to the 10th month. Associations between the SU of each added ingredient with infant feeding and caregiving practices were studied with multivariable linear regressions adjusted for familial characteristics. Only 28% of the parents followed the recommendation of adding fat and simultaneously not adding sugar or salt. Breastfeeding mothers were more prone to add sugar, salt, and fat than non-breastfeeding mothers. CFI before four months was positively associated with the SU of added sugar and salt and negatively associated with the SU of added fat. The use of commercial baby food was negatively related to the SU of added salt and fat. The use of these added ingredients was mainly related to breastfeeding, age at CFI, and use of commercial food, and it was independent of the household socioeconomic characteristics.

Published
2019
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30. Factors associated with the introduction of complementary feeding in the French ELFE cohort study.

Author

Bournez M, Ksiazek E, Wagner S, Kersuzan C, Tichit C, Gojard S, Thierry X, Charles MA, Lioret S, de Lauzon-Guillain B, and Nicklaus S

Subjects
Adult, Age Factors, Cohort Studies, Female, France, Humans, Infant, Interviews as Topic, Longitudinal Studies, Male, Sex Factors, Socioeconomic Factors, Young Adult, Breast Feeding statistics & numerical data, Infant Food statistics & numerical data, Infant Nutritional Physiological Phenomena
Abstract

The objectives of this study were to estimate the age of complementary feeding introduction (CFI) and investigate the related health, demographic, and socio-economic factors. Analyses were based on 10,931 infants from the French national birth cohort ELFE, born in 2011. Health, demographic, and socio-economic data concerning infants and parents were collected at birth (face-to-face interviews and medical records) and 2 months (telephone interviews). Data on milk feeding and CFI practices were collected at birth and 2 months then monthly from 3 to 10 months using online or paper questionnaires. The associations between both health and social factors and CFI age were tested by multivariable multinomial logistic regressions. The mean CFI age was 5.2 ± 1.2 months; 26% of the infants started complementary feeding before 4 months of age (CF < 4 months), 62% between 4 and 6 months of age, and 12% after 6 months of age (CF > 6 months). CF < 4 months was more likely when mothers smoked, were overweight/obese, younger (<29 years), and used their personal experience as an information source in child caregiving and when both parents were not born in France. CF < 4 months was less likely when the infant was a girl, second-born, when the mother breastfed longer, and had attended at least one birth preparation class. Mothers of second-born infants and who breastfed their child longer were more likely to introduce CF > 6 months. Couples in which fathers were born in France and mothers were not born in France were less likely to introduce CF > 6 months. CF < 4 months occurred in more than 25% of the cases. It is important to continue promoting clear CFI recommendations, especially in smoking, overweight, young, not born in France, and nonbreastfeeding mothers., (© 2017 John Wiley & Sons Ltd.)

Published
2018
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31. Use of infant formula in the ELFE study: The association with social and health-related factors.

Author

de Lauzon-Guillain B, Davisse-Paturet C, Lioret S, Ksiazek E, Bois C, Dufourg MN, Bournez M, Nicklaus S, Wagner S, and Charles MA

Subjects
Adult, Breast Feeding ethnology, Cohort Studies, Educational Status, Female, France, Humans, Infant, Newborn, Longitudinal Studies, Male, Nutrition Surveys, Prebiotics administration & dosage, Probiotics chemistry, Probiotics therapeutic use, Prospective Studies, Protein Hydrolysates chemistry, Socioeconomic Factors, Viscosity, Women, Working, Child Development, Family Characteristics, Feeding Methods, Food Intolerance diet therapy, Infant Formula adverse effects, Infant Formula chemistry, Infant Formula microbiology, Infant Nutritional Physiological Phenomena ethnology, Protein Hydrolysates therapeutic use
Abstract

Breastfeeding is recommended until 6 months of age, but a wide range of infant formula is available for nonbreastfed or partially breastfed infants. Our aim was to describe infant formula selection and to examine social- and health-related factors associated with this selection. Analyses were based on 13,291 infants from the French national birth cohort Etude Longitudinale Française depuis l'Enfance. Infant diet was assessed at Month 2 by phone interview and monthly from Months 3 to 10 via internet/paper questionnaires. Infant formulas were categorized in 6 groups: extensively or partially hydrolysed, regular with or without prebiotics/probiotics, and thickened with or without prebiotics/probiotics. Associations between type of infant formula used at 2 months and family or infant characteristics were assessed by multinomial logistic regressions. At Month 2, 58.1% of formula-fed infants were fed with formula enriched in prebiotics/probiotics, 31.5% with thickened formula, and 1.4% with extensively hydrolysed formula. The proportion of formula-fed infants increased regularly, but the type of infant formula used was fairly stable between 2 and 10 months. At Month 2, extensively hydrolysed formulas were more likely to be used in infants with diarrhoea or regurgitation problems. Partially hydrolysed formulas were more often used in families with high income, with a history of allergy, or with infants with regurgitation issues. Thickened formulas were used more with boys, preterm infants, infants with regurgitation issues, or in cases of early maternal return to work. The main factors related to the selection of infant formula were family and infant health-related ones., (© 2017 John Wiley & Sons Ltd.)

Published
2018
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32. Do hedonic- versus nutrition-based attitudes toward food predict food choices? a cross-sectional study of 6- to 11-year-olds.

Author

Marty L, Miguet M, Bournez M, Nicklaus S, Chambaron S, and Monnery-Patris S

Subjects
Body Mass Index, Child, Cross-Sectional Studies, Diet, Healthy, Female, France, Humans, Male, Nutritional Status, Nutritive Value, Pleasure, Reproducibility of Results, Choice Behavior, Food Preferences psychology, Health Knowledge, Attitudes, Practice
Abstract

Background: Implicit and explicit attitudes are potential precursors of food choices and combine affective and cognitive components that can vary in their relative dominance. Yet, the affective and cognitive components of attitudes toward food can lead to distinct predisposition toward a food item and potentially to different food choices. In the food domain, the affective component pertains to the hedonic tone of consumption, while the cognitive component encompasses nutritional value or health consequences of food. The present study investigated whether hedonic- versus nutrition-based implicit and/or explicit attitudes toward food predicts children's healthy versus unhealthy food choices., Methods: A total of 63 children (age range = 6.3-11.5) participated in a 90-min session at 5 pm (i.e., afterschool snack time in France). The children were asked to choose five food items from a buffet featuring five healthy and five unhealthy sweet foods pretested as being highly liked. Children ate what they had chosen. Moreover, their implicit attitudes were assessed with a pairing task in which children were presented with 10 food triplets and asked to choose two food items that "best go together". For each triplet, foods could be paired according to their hedonic or nutritional characteristics. Explicit attitudes were assessed with a task in which children placed each of 48 food items into one of the following categories: "yummy", "yucky" (i.e., hedonic categories), "makes you strong", or "makes you fat" (i.e., nutritional categories)., Results: Both implicit and explicit attitudes significantly influenced children's food choices. We observed that children with more hedonic-based implicit or explicit attitudes toward food were more likely to choose healthy food options from the buffet. Conversely, children with both implicit and explicit nutrition-based attitudes chose less healthy foods., Conclusions: Hedonic-based attitudes toward food seem to drive healthier food choices in children compared with nutrition-based attitudes in this particular eating context. These findings suggest that pleasure from eating might be an ally with regard to healthy eating among children. Additional research is needed to understand the etiology of children's attitudes toward food in order to provide insights on how to shape adequate children's attitudes to guide them toward healthy food choices.

Published
2017
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