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1. A new ISO standard for the experimental characterization of in-plane permeability of fibrous reinforcements

Author

May, D., Advani, S.G., Duhovic, M., Endruweit, A., Fauster, E., George, A., Liotier, P.-J., Lira, C., Lomov, S.V., Pucci, M.F., Schmeer, S., Abliz, D., Berg, D.C., Binetruy, C., Bodaghi, M., Comas-Cardona, S., Etchells, M., Govignon, Q., Koorevaar, A., Michaud, V., Park, C.H., Schubnel, R., Sousa, P., Ravel, R., Rouhi, M., Syerko, E., Umer, R., Vollmer, M., and Yong, A.

Published
2025
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2. Towards standardisation of the out-of-plane permeability measurement for reinforcement textiles

Author

Yong, A.X.H., Endruweit, A., George, A., May, D., Aksoy, Y.A., Ali, M.A., Allen, T., Baral, P., Betteridge, C., Brauner, C., Caglar, B., Chiminelli, A., Cracknell, D., Dame, L., Dittmann, J., Dransfeld, C., Drapier, S., García Manrique, J.A., Garrigou, E., Guilloux, A., Hubert, P., Ivens, J., Janzen, J., Khan, T., Kikuta, H., Kind, K., Laspalas, M., Lee, J., Liu, X., Lizaranzu, M., Lomov, S.V., Masania, K., Michaud, V., Middendorf, P., Miguel, S., Muñoz, J., Narayana, S.S., Park, C.H., Pedoto, G., Pisupati, A., Sayinbas, D., Sousa, P., Sozer, M., Staal, J., Steinhardt, M., Teixido, H., Umer, R., Vincent, J.D., Werlen, V., and Yuksel, O.

Published
2025
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3. Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia

Author

Saettini, F, Guerra, F, Mauri, M, Salter, C, Adam, M, Adams, D, Baple, E, Barredo, E, Bhatia, S, Borkhardt, A, Brusco, A, Bugarin, C, Chinello, C, Crosby, A, D'Souza, P, Denti, V, Fazio, G, Giuliani, S, Kuehn, H, Amel, H, Elmi, A, Lo, B, Malighetti, F, Mandrile, G, Martín-Nalda, A, Mefford, H, Moratto, D, Emam Mousavi, F, Nelson, Z, Gutiérrez-Solana, L, Macnamara, E, Michaud, V, O'Leary, M, Pagani, L, Pavinato, L, Santamaria, P, Planas-Serra, L, Quadri, M, Raspall-Chaure, M, Rebellato, S, Rosenzweig, S, Roubertie, A, Holzinger, D, Deal, C, Vockley, C, Savino, A, L. Stoddard, J, Uhlig, H, Pujol, A, Magni, F, Paglia, G, Cazzaniga, G, Piazza, R, Barberis, M, Biondi, A, Saettini, Francesco, Guerra, Fabiola, Mauri, Mario, Salter, Claire G., Adam, Margaret P., Adams, David, Baple, Emma L., Barredo, Estibaliz, Bhatia, Sanil, Borkhardt, Arndt, Brusco, Alfredo, Bugarin, Cristina, Chinello, Clizia, Crosby, Andrew H., D'Souza, Precilla, Denti, Vanna, Fazio, Grazia, Giuliani, Silvia, Kuehn, Hye Sun, Amel, Hassan, Elmi, Asha, Lo, Bernice, Malighetti, Federica, Mandrile, Giorgia, Martín-Nalda, Andrea, Mefford, Heather C., Moratto, Daniele, Emam Mousavi, Fatemeh, Nelson, Zoe, Gutiérrez-Solana, Luis González, Macnamara, Ellen, Michaud, Vincent, O'Leary, Melanie, Pagani, Lisa, Pavinato, Lisa, Santamaria, Patricia VVelez, Planas-Serra, Laura, Quadri, Manuel, Raspall-Chaure, Miquel, Rebellato, Stefano, Rosenzweig, Sergio D., Roubertie, Agathe, Holzinger, Dirk, Deal, Christin, Vockley, Catherine Walsh, Savino, Angela Maria, L. Stoddard, Jennifer, Uhlig, Holm H., Pujol, Aurora, Magni, Fulvio, Paglia, Giuseppe, Cazzaniga, Gianni, Piazza, Rocco, Barberis, Matteo, Biondi, Andrea, Saettini, F, Guerra, F, Mauri, M, Salter, C, Adam, M, Adams, D, Baple, E, Barredo, E, Bhatia, S, Borkhardt, A, Brusco, A, Bugarin, C, Chinello, C, Crosby, A, D'Souza, P, Denti, V, Fazio, G, Giuliani, S, Kuehn, H, Amel, H, Elmi, A, Lo, B, Malighetti, F, Mandrile, G, Martín-Nalda, A, Mefford, H, Moratto, D, Emam Mousavi, F, Nelson, Z, Gutiérrez-Solana, L, Macnamara, E, Michaud, V, O'Leary, M, Pagani, L, Pavinato, L, Santamaria, P, Planas-Serra, L, Quadri, M, Raspall-Chaure, M, Rebellato, S, Rosenzweig, S, Roubertie, A, Holzinger, D, Deal, C, Vockley, C, Savino, A, L. Stoddard, J, Uhlig, H, Pujol, A, Magni, F, Paglia, G, Cazzaniga, G, Piazza, R, Barberis, M, Biondi, A, Saettini, Francesco, Guerra, Fabiola, Mauri, Mario, Salter, Claire G., Adam, Margaret P., Adams, David, Baple, Emma L., Barredo, Estibaliz, Bhatia, Sanil, Borkhardt, Arndt, Brusco, Alfredo, Bugarin, Cristina, Chinello, Clizia, Crosby, Andrew H., D'Souza, Precilla, Denti, Vanna, Fazio, Grazia, Giuliani, Silvia, Kuehn, Hye Sun, Amel, Hassan, Elmi, Asha, Lo, Bernice, Malighetti, Federica, Mandrile, Giorgia, Martín-Nalda, Andrea, Mefford, Heather C., Moratto, Daniele, Emam Mousavi, Fatemeh, Nelson, Zoe, Gutiérrez-Solana, Luis González, Macnamara, Ellen, Michaud, Vincent, O'Leary, Melanie, Pagani, Lisa, Pavinato, Lisa, Santamaria, Patricia VVelez, Planas-Serra, Laura, Quadri, Manuel, Raspall-Chaure, Miquel, Rebellato, Stefano, Rosenzweig, Sergio D., Roubertie, Agathe, Holzinger, Dirk, Deal, Christin, Vockley, Catherine Walsh, Savino, Angela Maria, L. Stoddard, Jennifer, Uhlig, Holm H., Pujol, Aurora, Magni, Fulvio, Paglia, Giuseppe, Cazzaniga, Gianni, Piazza, Rocco, Barberis, Matteo, and Biondi, Andrea

Abstract

Purpose PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells. Methods Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells. Results Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization. Conclusion By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related dis

Published
2025

4. Benchmark exercise on image-based permeability determination of engineering textiles: Microscale predictions

Author

Syerko, E., Schmidt, T., May, D., Binetruy, C., Advani, S.G., Lomov, S., Silva, L., Abaimov, S., Aissa, N., Akhatov, I., Ali, M., Asiaban, N., Broggi, G., Bruchon, J., Caglar, B., Digonnet, H., Dittmann, J., Drapier, S., Endruweit, A., Guilloux, A., Kandinskii, R., Leygue, A., Mahato, B., Martínez-Lera, P., Matveev, M., Michaud, V., Middendorf, P., Moulin, N., Orgéas, L., Park, C.H., Rief, S., Rouhi, M., Sergeichev, I., Shakoor, M., Shishkina, O., Swolfs, Y., Tahani, M., Umer, R., Vanclooster, K., and Vorobyev, R.

Published
2023
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5. Utilizing Pharmacogenomics Results to Determine Opioid Appropriateness and Improve Pain Management in a Patient with Osteoarthritis

Author

Pizzolato K, Thacker D, Del Toro-Pagán NM, Amin NS, Hanna A, Turgeon J, and Michaud V

Subjects
cyp2d6, cyp2c9, drug-gene interactions, opioids, pain management, pharmacogenomics, Therapeutics. Pharmacology, RM1-950
Abstract

Katie Pizzolato,1 David Thacker,2 Nicole Marie Del Toro-Pagán,1 Nishita S Amin,1 Abeer Hanna,3 Jacques Turgeon,2,4 Veronique Michaud2,4,5 1Tabula Rasa Healthcare, Office of Translational Research and Residency Programs, Moorestown, NJ, 08057, USA; 2Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Orlando, FL, 32827, USA; 3VieCare Butler, Program of All-Inclusive Care for the Elderly (PACE), Butler, PA, 16001, USA; 4Faculty of Pharmacy, Université de Montréal, Montréal, QC, H2L, Canada; 5University of Montreal Hospital Research Center (CRCHUM), Montréal, QC, H2X 0A9, CanadaCorrespondence: Veronique Michaud, Precision Pharmacotherapy Research and Development Institute, 13485 Veterans Way, Orlando, FL, 32827, USA, Tel +856-938-8697, Email vmichaud@trhc.comAbstract: The opioid epidemic in the United States has exposed the need for providers to limit opioid dispensing and identify at-risk patients prior to prescribing opioids. With pharmacogenomic testing, clinicians can analyze hundreds of medications—including commonly prescribed opioids—against genetic results to understand and predict risk and response. Moreover, knowledge of genotypic variants and altered function can help decrease trial and error prescribing, identify patients at-risk for adverse drug events, and improve pain control. This patient case demonstrates how pharmacogenomic test results identified drug–gene interactions and provided insight about a patient’s inadequate opioid therapy response. With pharmacogenomic information, the patient’s healthcare team discontinued opioid therapy and selected a more appropriate regimen for osteoarthritis (ie, celecoxib), resulting in improved pain control and quality of life.Keywords: CYP2D6, CYP2C9, drug–gene interactions, opioids, pain management, pharmacogenomics

Published
2022

7. Out-of-plane permeability measurement for reinforcement textiles: A benchmark exercise

Author

Yong, A.X.H., Aktas, A., May, D., Endruweit, A., Advani, S., Hubert, P., Abaimov, S.G., Abliz, D., Akhatov, I., Ali, M.A., Allen, T., Berg, D.C., Bickerton, S., Brauner, C., Brütsch, D., Caglar, B., Caglar, H., Causse, P., Chiminelli, A., Cohades, A., Comas-Cardona, S., Danzi, M., Dittmann, J., Dransfeld, C., Ermanni, P., Fauster, E., Garcia-Manrique, J.A., George, A., Graupner, R., Grishaev, V., Guilloux, A., Hancioglu, M., Harizi, W., Herman, T., Huang, W., Kabachi, M.A., Keller, A., Kind, K., Laspalas, M., Lebedev, O.V., Lizaranzu, M., Long, A.C., Masania, K., Michaud, V., Middendorf, P., Salvatori, D., Schubnel, R., Sharp, N., Sozer, M., Thomas, J., Trochu, F., Umer, R., Valette, J., Wang, J.H., and Willenbacher, B.

Published
2021
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8. Experimental characterisation of textile compaction response: A benchmark exercise

Author

Yong, A.X.H., Aktas, A., May, D., Endruweit, A., Lomov, S.V., Advani, S., Hubert, P., Abaimov, S.G., Abliz, D., Akhatov, I., Ali, M.A., Allaoui, S., Allen, T., Berg, D.C., Bickerton, S., Caglar, B., Causse, P., Chiminelli, A., Comas-Cardona, S., Danzi, M., Dittmann, J., Dransfeld, C., Ermanni, P., Fauster, E., George, A., Gillibert, J., Govignon, Q., Graupner, R., Grishaev, V., Guilloux, A., Kabachi, M.A., Keller, A., Kind, K., Large, D., Laspalas, M., Lebedev, O.V., Lizaranzu, M., Long, A.C., López, C., Masania, K., Michaud, V., Middendorf, P., Mitschang, P., van Oosterom, S., Schubnel, R., Sharp, N., Sousa, P., Trochu, F., Umer, R., Valette, J., and Wang, J.H.

Published
2021
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13. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Palmer, EE ; https://orcid.org/0000-0003-1844-215X, Pusch, M, Picollo, A, Forwood, C, Nguyen, MH ; https://orcid.org/0000-0002-2529-5330, Suckow, V, Gibbons, J, Hoff, A, Sigfrid, L, Megarbane, A, Nizon, M, Cogné, B, Beneteau, C, Alkuraya, FS, Chedrawi, A, Hashem, MO, Stamberger, H, Weckhuysen, S, Vanlander, A, Ceulemans, B, Rajagopalan, S, Nunn, K, Arpin, S, Raynaud, M, Motter, CS, Ward-Melver, C, Janssens, K, Meuwissen, M, Beysen, D, Dikow, N, Grimmel, M, Haack, TB, Clement, E, McTague, A, Hunt, D, Townshend, S, Ward, M, Richards, LJ, Simons, C, Costain, G, Dupuis, L, Mendoza-Londono, R, Dudding-Byth, T, Boyle, J, Saunders, C, Fleming, E, El Chehadeh, S, Spitz, MA, Piton, A, Gerard, B, Abi Warde, MT, Rea, G, McKenna, C, Douzgou, S, Banka, S, Akman, C, Bain, JM, Sands, TT, Wilson, GN, Silvertooth, EJ, Miller, L, Lederer, D, Sachdev, R, Macintosh, R ; https://orcid.org/0000-0001-5036-0264, Monestier, O, Karadurmus, D, Collins, F, Carter, M, Rohena, L, Willemsen, MH, Ockeloen, CW, Pfundt, R, Kroft, SD, Field, M, Laranjeira, FER, Fortuna, AM, Soares, AR, Michaud, V, Naudion, S, Golla, S, Weaver, DD, Bird, LM, Friedman, J, Clowes, V, Joss, S, Pölsler, L, Campeau, PM, Blazo, M, Bijlsma, EK, Rosenfeld, JA, Beetz, C, Powis, Z, McWalter, K, Brandt, T, Torti, E, Mathot, M, Mohammad, SS, Armstrong, R, Kalscheuer, VM, Palmer, EE ; https://orcid.org/0000-0003-1844-215X, Pusch, M, Picollo, A, Forwood, C, Nguyen, MH ; https://orcid.org/0000-0002-2529-5330, Suckow, V, Gibbons, J, Hoff, A, Sigfrid, L, Megarbane, A, Nizon, M, Cogné, B, Beneteau, C, Alkuraya, FS, Chedrawi, A, Hashem, MO, Stamberger, H, Weckhuysen, S, Vanlander, A, Ceulemans, B, Rajagopalan, S, Nunn, K, Arpin, S, Raynaud, M, Motter, CS, Ward-Melver, C, Janssens, K, Meuwissen, M, Beysen, D, Dikow, N, Grimmel, M, Haack, TB, Clement, E, McTague, A, Hunt, D, Townshend, S, Ward, M, Richards, LJ, Simons, C, Costain, G, Dupuis, L, Mendoza-Londono, R, Dudding-Byth, T, Boyle, J, Saunders, C, Fleming, E, El Chehadeh, S, Spitz, MA, Piton, A, Gerard, B, Abi Warde, MT, Rea, G, McKenna, C, Douzgou, S, Banka, S, Akman, C, Bain, JM, Sands, TT, Wilson, GN, Silvertooth, EJ, Miller, L, Lederer, D, Sachdev, R, Macintosh, R ; https://orcid.org/0000-0001-5036-0264, Monestier, O, Karadurmus, D, Collins, F, Carter, M, Rohena, L, Willemsen, MH, Ockeloen, CW, Pfundt, R, Kroft, SD, Field, M, Laranjeira, FER, Fortuna, AM, Soares, AR, Michaud, V, Naudion, S, Golla, S, Weaver, DD, Bird, LM, Friedman, J, Clowes, V, Joss, S, Pölsler, L, Campeau, PM, Blazo, M, Bijlsma, EK, Rosenfeld, JA, Beetz, C, Powis, Z, McWalter, K, Brandt, T, Torti, E, Mathot, M, Mohammad, SS, Armstrong, R, and Kalscheuer, VM

Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

14. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., Kalscheuer, V.M., Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., and Kalscheuer, V.M.

Abstract

01 februari 2023, Item does not contain fulltext, Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

15. Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

Author

Jaarsveld, R.H. van, Reilly, J., Cornips, M.C., Hadders, M.A., Agolini, E., Ahimaz, P., Anyane-Yeboa, K., Bellanger, S.A., Binsbergen, E. van, Boogaard, M.J. van den, Brischoux-Boucher, E., Caylor, R.C., Ciolfi, A., Essen, T.A. van, Fontana, P., Hopman, S., Iascone, M., Javier, M.M., Kamsteeg, E.J., Kerkhof, J., Kido, J., Kim, H.G., Kleefstra, T., Lonardo, F., Lai, A., Lev, D., Levy, M.A., Lewis, M.E.S., Lichty, A., Mannens, M.M., Matsumoto, N., Maya, I., McConkey, H., Megarbane, A., Michaud, V., Miele, E., Niceta, M., Novelli, A., Onesimo, R., Pfundt, R.P., Popp, B., Prijoles, E., Relator, R., Redon, S., Rots, D., Rouault, K., Saida, K., Schieving, J.H., Tartaglia, M., Tenconi, R., Uguen, K., Verbeek, N., Walsh, C.A., Yosovich, K., Yuskaitis, C.J., Zampino, G., Sadikovic, B., Alders, M., Oegema, R., Jaarsveld, R.H. van, Reilly, J., Cornips, M.C., Hadders, M.A., Agolini, E., Ahimaz, P., Anyane-Yeboa, K., Bellanger, S.A., Binsbergen, E. van, Boogaard, M.J. van den, Brischoux-Boucher, E., Caylor, R.C., Ciolfi, A., Essen, T.A. van, Fontana, P., Hopman, S., Iascone, M., Javier, M.M., Kamsteeg, E.J., Kerkhof, J., Kido, J., Kim, H.G., Kleefstra, T., Lonardo, F., Lai, A., Lev, D., Levy, M.A., Lewis, M.E.S., Lichty, A., Mannens, M.M., Matsumoto, N., Maya, I., McConkey, H., Megarbane, A., Michaud, V., Miele, E., Niceta, M., Novelli, A., Onesimo, R., Pfundt, R.P., Popp, B., Prijoles, E., Relator, R., Redon, S., Rots, D., Rouault, K., Saida, K., Schieving, J.H., Tartaglia, M., Tenconi, R., Uguen, K., Verbeek, N., Walsh, C.A., Yosovich, K., Yuskaitis, C.J., Zampino, G., Sadikovic, B., Alders, M., and Oegema, R.

Abstract

01 januari 2023, Item does not contain fulltext, PURPOSE: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. METHODS: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. RESULTS: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.

Published
2023

16. KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties

Author

Cioclu, M.C., Mosca, I., Ambrosino, P., Puzo, D., Bayat, A., Wortmann, S.B., Koch, J., Strehlow, V., Shirai, K., Matsumoto, N., Sanders, S.J., Michaud, V., Legendre, M., Riva, A., Striano, P., Muhle, H., Pendziwiat, M., Lesca, G., Mangano, G.D., Nardello, R., Lemke, J.R., Møller, R.S., Soldovieri, M.V., Kamsteeg, E.J., Rubboli, G., Taglialatela, M., Cioclu, M.C., Mosca, I., Ambrosino, P., Puzo, D., Bayat, A., Wortmann, S.B., Koch, J., Strehlow, V., Shirai, K., Matsumoto, N., Sanders, S.J., Michaud, V., Legendre, M., Riva, A., Striano, P., Muhle, H., Pendziwiat, M., Lesca, G., Mangano, G.D., Nardello, R., Lemke, J.R., Møller, R.S., Soldovieri, M.V., Kamsteeg, E.J., Rubboli, G., and Taglialatela, M.

Abstract

Item does not contain fulltext, OBJECTIVE: Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants. METHODS: Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells. RESULTS: The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others. INTERPRETATION: We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332-349.

Published
2023

20. Experimental determination of the permeability of engineering textiles: Benchmark II

Author

Vernet, N., Ruiz, E., Advani, S., Alms, J.B., Aubert, M., Barburski, M., Barari, B., Beraud, J.M., Berg, D.C., Correia, N., Danzi, M., Delavière, T., Dickert, M., Di Fratta, C., Endruweit, A., Ermanni, P., Francucci, G., Garcia, J.A., George, A., Hahn, C., Klunker, F., Lomov, S.V., Long, A., Louis, B., Maldonado, J., Meier, R., Michaud, V., Perrin, H., Pillai, K., Rodriguez, E., Trochu, F., Verheyden, S., Wietgrefe, M., Xiong, W., Zaremba, S., and Ziegmann, G.

Published
2014
Full Text
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28. Foveal hypoplasia in parents of patients with albinism

Author

Lejoyeux, R., primary, Alonso, A-S, additional, Lafolie, J., additional, Michaud, V., additional, Lasseaux, E., additional, Vasseur, V., additional, Derrien, S., additional, Robert, M. P., additional, Le Mer, Y., additional, Tadayoni, R., additional, Arveiler, B., additional, and Mauget-Faÿsse, M., additional

Published
2022
Full Text
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29. KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism

Author

Miceli, F., Millevert, C., Soldovieri, M.V., Mosca, I., Ambrosino, P., Carotenuto, L., Schrader, D., Lee, H.K., Riviello, J., Hong, W., Risen, S., Emrick, L., Amin, H., Ville, D. Van De, Edery, P., Bellescize, J. de, Michaud, V., Van-Gils, J., Goizet, C., Willemsen, M.H., Kleefstra, T., Møller, R.S., Bayat, A., Devinsky, O., Sands, T., Korenke, G.C., Kluger, G., Mefford, H.C., Brilstra, E., Lesca, G., Milh, M., Cooper, E.C., Taglialatela, M., Weckhuysen, S., Miceli, F., Millevert, C., Soldovieri, M.V., Mosca, I., Ambrosino, P., Carotenuto, L., Schrader, D., Lee, H.K., Riviello, J., Hong, W., Risen, S., Emrick, L., Amin, H., Ville, D. Van De, Edery, P., Bellescize, J. de, Michaud, V., Van-Gils, J., Goizet, C., Willemsen, M.H., Kleefstra, T., Møller, R.S., Bayat, A., Devinsky, O., Sands, T., Korenke, G.C., Kluger, G., Mefford, H.C., Brilstra, E., Lesca, G., Milh, M., Cooper, E.C., Taglialatela, M., and Weckhuysen, S.

Abstract

Contains fulltext : 284811.pdf (Publisher’s version ) (Open Access), BACKGROUND: Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. METHODS: Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. FINDINGS: Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. INTERPRETATION: Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. FUNDING: Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University

Published
2022

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