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1. Pushing the boundaries of rare disease diagnostics with the help of the first Undiagnosed Hackathon

Author

Delgado-Vega, Angelica Maria, Cederroth, Helene, Taylan, Fulya, Ekholm, Katja, Ek, Marlene, Thonberg, Håkan, Jemt, Anders, Nilsson, Daniel, Eisfeldt, Jesper, Bilgrav Saether, Kristine, Höijer, Ida, Akgun-Dogan, Ozlem, Asano, Yui, Barakat, Tahsin Stefan, Batkovskyte, Dominyka, Baynam, Gareth, Bodamer, Olaf, Chetruengchai, Wanna, Corcoran, Pádraic, Couse, Madeline, Danis, Daniel, Demidov, German, Dohi, Eisuke, Erhardsson, Mattias, Fernandez-Luna, Luis, Fujiwara, Toyofumi, Garg, Neha, Giugliani, Roberto, Gonzaga-Jauregui, Claudia, Grigelioniene, Giedre, Groza, Tudor, Gunnarsson, Cecilia, Hammarsjö, Anna, Hammond, Charles Kumi, Hatirnaz Ng, Özden, Hesketh, Sirisha, Hettiarachchi, Dineshani, Johansson Soller, Maria, Kirmani, Umn Ahmed, Kjellberg, Martin, Kvarnung, Malin, Kvlividze, Oleg, Lagerstedt-Robinson, Kristina, Lasko, Paul, Lassmann, Timo, Lau, Lynette Y. S., Laurie, Steven, Lim, Weng Khong, Liu, Zhandong, Lysenkova Wiklander, Mariya, Makay, Prince, Maiga, Alassane Baneye, Maya-González, Carolina, Meyn, M. Stephen, Neethiraj, Ramprasad, Nigro, Vincenzo, Nordgren, Felix, Nordlund, Jessica, Orrsjö, Sara, Ottosson, Jesper, Ozbek, Ugur, Özdemir, Özkan, Partin, Clyde, Pearce, David A., Peck, Raquel, Pedersen, Annie, Pettersson, Maria, Pongpanich, Monnat, Posada de la Paz, Manuel, Ramani, Arun, Romero, Juan Andres, Romero, Vanessa I., Rosenquist, Richard, Saw, Aung Min, Spencer, Matthew, Stattin, Eva-Lena, Srichomthong, Chalurmpon, Tapia-Paez, Isabel, Taruscio, Domenica, Taylor, Julie P., Tkemaladze, Tinatin, Tully, Ian, Tümer, Zeynep, van Zelst-Stams, Wendy A. G., Verloes, Alain, Västerviga, Emma, Wang, Sailan, Yang, Rachel, Yamamoto, Shinya, Yépez, Vicente A., Zhang, Qing, Shotelersuk, Vorasuk, Wiafe, Samuel Agyei, Alanay, Yasemin, Botto, Lorenzo D., Kirmani, Salman, Lumaka, Aimé, Palmer, Elizabeth Emma, Puri, Ratna Dua, Wirta, Valtteri, Lindstrand, Anna, Buske, Orion J., Cederroth, Mikk, and Nordgren, Ann

Published
2024
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4. A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis

Author

Justice, Cristina M, Cuellar, Araceli, Bala, Krithi, Sabourin, Jeremy A, Cunningham, Michael L, Crawford, Karen, Phipps, Julie M, Zhou, Yan, Cilliers, Deirdre, Byren, Jo C, Johnson, David, Wall, Steven A, Morton, Jenny EV, Noons, Peter, Sweeney, Elizabeth, Weber, Astrid, Rees, Katie EM, Wilson, Louise C, Simeonov, Emil, Kaneva, Radka, Yaneva, Nadezhda, Georgiev, Kiril, Bussarsky, Assen, Senders, Craig, Zwienenberg, Marike, Boggan, James, Roscioli, Tony, Tamburrini, Gianpiero, Barba, Marta, Conway, Kristin, Sheffield, Val C, Brody, Lawrence, Mills, James L, Kay, Denise, Sicko, Robert J, Langlois, Peter H, Tittle, Rachel K, Botto, Lorenzo D, Jenkins, Mary M, LaSalle, Janine M, Lattanzi, Wanda, Wilkie, Andrew OM, Wilson, Alexander F, Romitti, Paul A, and Boyadjiev, Simeon A

Subjects
Genetics, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10–8): rs781716 (P = 4.71 × 10–9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10–8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10–9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10–8, OR = 0.45; P = 3.31 × 10–8, OR = 0.45; P = 1.09 × 10–8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10–8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10–6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821–55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

Published
2020

5. SLC35A2‐CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

Author

Ng, Bobby G, Sosicka, Paulina, Agadi, Satish, Almannai, Mohammed, Bacino, Carlos A, Barone, Rita, Botto, Lorenzo D, Burton, Jennifer E, Carlston, Colleen, Chung, Brian Hon‐Yin, Cohen, Julie S, Coman, David, Dipple, Katrina M, Dorrani, Naghmeh, Dobyns, William B, Elias, Abdallah F, Epstein, Leon, Gahl, William A, Garozzo, Domenico, Hammer, Trine Bjørg, Haven, Jaclyn, Héron, Delphine, Herzog, Matthew, Hoganson, George E, Hunter, Jesse M, Jain, Mahim, Juusola, Jane, Lakhani, Shenela, Lee, Hane, Lee, Joy, Lewis, Katherine, Longo, Nicola, Lourenço, Charles Marques, Mak, Christopher CY, McKnight, Dianalee, Mendelsohn, Bryce A, Mignot, Cyril, Mirzaa, Ghayda, Mitchell, Wendy, Muhle, Hiltrud, Nelson, Stanley F, Olczak, Mariusz, Palmer, Christina GS, Partikian, Arthur, Patterson, Marc C, Pierson, Tyler M, Quinonez, Shane C, Regan, Brigid M, Ross, M Elizabeth, Sacoto, Maria J Guillen, Scaglia, Fernando, Scheffer, Ingrid E, Segal, Devorah, Singhal, Nilika Shah, Striano, Pasquale, Sturiale, Luisa, Symonds, Joseph D, Tang, Sha, Vilain, Eric, Willis, Mary, Wolfe, Lynne A, Yang, Hui, Yano, Shoji, Powis, Zöe, Suchy, Sharon F, Rosenfeld, Jill A, Edmondson, Andrew C, Grunewald, Stephanie, and Freeze, Hudson H

Subjects
Clinical Research, Pediatric, Genetics, Aetiology, 2.1 Biological and endogenous factors, Animals, Biopsy, CHO Cells, Cells, Cultured, Congenital Disorders of Glycosylation, Cricetulus, Female, Humans, Male, Monosaccharide Transport Proteins, Mutation, Uridine Diphosphate Galactose, congenital disorders of glycosylation, glycoside, nucleotide sugar transporter, UDP-galactose, Clinical Sciences, Genetics & Heredity
Abstract

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Published
2019

6. Public Health Approach to Improve Outcomes for Congenital Heart Disease Across the Life Span

Author

Jenkins, Kathy J, Botto, Lorenzo D, Correa, Adolfo, Foster, Elyse, Kupiec, Jennifer K, Marino, Bradley S, Oster, Matthew E, Stout, Karen K, and Honein, Margaret A

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Health Services Accessibility, Heart Defects, Congenital, Humans, Primary Prevention, Public Health Administration, Secondary Prevention, United States, congenital heart disease, public health, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Published
2019

7. Preventing birth defects, saving lives, and promoting health equity: an urgent call to action for universal mandatory food fortification with folic acid

Author

Kancherla, Vijaya, Botto, Lorenzo D, Rowe, Laura A, Shlobin, Nathan A, Caceres, Adrian, Arynchyna-Smith, Anastasia, Zimmerman, Kathrin, Blount, Jeffrey, Kibruyisfaw, Zewdie, Ghotme, Kemel A, Karmarkar, Santosh, Fieggen, Graham, Roozen, Sylvia, Oakley, Godfrey P, Jr, Rosseau, Gail, and Berry, Robert J

Published
2022
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8. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author

Helbig, Katherine L, Lauerer, Robert J, Bahr, Jacqueline C, Souza, Ivana A, Myers, Candace T, Uysal, Betül, Schwarz, Niklas, Gandini, Maria A, Huang, Sun, Keren, Boris, Mignot, Cyril, Afenjar, Alexandra, de Villemeur, Thierry Billette, Héron, Delphine, Nava, Caroline, Valence, Stéphanie, Buratti, Julien, Fagerberg, Christina R, Soerensen, Kristina P, Kibaek, Maria, Kamsteeg, Erik-Jan, Koolen, David A, Gunning, Boudewijn, Schelhaas, H Jurgen, Kruer, Michael C, Fox, Jordana, Bakhtiari, Somayeh, Jarrar, Randa, Padilla-Lopez, Sergio, Lindstrom, Kristin, Jin, Sheng Chih, Zeng, Xue, Bilguvar, Kaya, Papavasileiou, Antigone, Xing, Qinghe, Zhu, Changlian, Boysen, Katja, Vairo, Filippo, Lanpher, Brendan C, Klee, Eric W, Tillema, Jan-Mendelt, Payne, Eric T, Cousin, Margot A, Kruisselbrink, Teresa M, Wick, Myra J, Baker, Joshua, Haan, Eric, Smith, Nicholas, Sadeghpour, Azita, Davis, Erica E, Katsanis, Nicholas, Genomics, Task Force for Neonatal, Allori, Alexander, Angrist, Misha, Ashley, Patricia, Bidegain, Margarita, Boyd, Brita, Chambers, Eileen, Cope, Heidi, Cotten, C Michael, Curington, Theresa, Ellestad, Sarah, Fisher, Kimberley, French, Amanda, Gallentine, William, Goldberg, Ronald, Hill, Kevin, Kansagra, Sujay, Katsanis, Sara, Kurtzberg, Joanne, Marcus, Jeffrey, McDonald, Marie, Mikati, Mohammed, Miller, Stephen, Murtha, Amy, Perilla, Yezmin, Pizoli, Carolyn, Purves, Todd, Ross, Sherry, Smith, Edward, Wiener, John, Corbett, Mark A, MacLennan, Alastair H, Gecz, Jozef, Biskup, Saskia, Goldmann, Eva, Rodan, Lance H, Kichula, Elizabeth, Segal, Eric, Jackson, Kelly E, Asamoah, Alexander, Dimmock, David, McCarrier, Julie, Botto, Lorenzo D, Filloux, Francis, Tvrdik, Tatiana, and Cascino, Gregory D

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Neurodegenerative, Brain Disorders, Neurosciences, Epilepsy, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Adult, Calcium Channels, R-Type, Cation Transport Proteins, Child, Child, Preschool, Contracture, Dyskinesias, Female, Genetic Variation, Humans, Infant, Male, Megalencephaly, Neurodevelopmental Disorders, Spasms, Infantile, Task Force for Neonatal Genomics, Deciphering Developmental Disorders Study, CACNA1E, ion channel, arthrogryposis, calcium channel, epilepsy, Biological Sciences, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Published
2018

9. Brief Report: Pediatrician Perspectives Regarding Genetic Evaluations of Children with Autism Spectrum Disorder

Author

Rutz, Audrey, Dent, Karin M., Botto, Lorenzo D., Young, Paul C., and Carbone, Paul S.

Abstract

Despite current guidelines, few children with autism spectrum disorder (ASD) receive genetic evaluations. We surveyed Utah pediatricians to characterize the knowledge, beliefs, current practices and perceived barriers of pediatricians regarding genetic evaluation of children with ASD. We found over half lacked knowledge of current guidelines and many held beliefs about genetic evaluation that did not align with guidelines. Barriers were lack of insurance coverage for genetic evaluation/testing and long wait times to see geneticists. Pediatricians with beliefs aligned with guidelines and those aware of the role of genetic counselors were more likely to adhere to guidelines. Efforts to educate pediatricians are needed along with system level solutions regarding availability of geneticists and reimbursement for genetic testing.

Published
2019
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10. Gastroschisis prevalence patterns in 27 surveillance programs from 24 countries, International Clearinghouse for Birth Defects Surveillance and Research, 1980–2017

Author

Feldkamp, Marcia L., primary, Canfield, Mark A., additional, Krikov, Sergey, additional, Prieto‐Merino, David, additional, Šípek, Antonin, additional, LeLong, Nathalie, additional, Amar, Emmanuelle, additional, Rissmann, Anke, additional, Csaky‐Szunyogh, Melinda, additional, Tagliabue, Giovanna, additional, Pierini, Anna, additional, Gatt, Miriam, additional, Bergman, Jorieke E. H., additional, Szabova, Elena, additional, Bermejo‐Sánchez, Eva, additional, Tucker, David, additional, Dastgiri, Saeed, additional, Bidondo, María Paz, additional, Canessa, Aurora, additional, Zarante, Ignacio, additional, Hurtado‐Villa, Paula, additional, Martinez, Laura, additional, Mutchinick, Osvaldo M., additional, Camelo, Jorge Lopez, additional, Benavides‐Lara, Adriana, additional, Thomas, Mary Ann, additional, Liu, Shiliang, additional, Nembhard, Wendy N., additional, Gray, Elizabeth B., additional, Nance, Amy E., additional, Mastroiacovo, Pierpaolo, additional, and Botto, Lorenzo D., additional

Published
2024
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13. Novel molecular mechanism in Malan syndrome uncovered through genome sequencing reanalysis, exon‐level Array, and RNA sequencing.

Author

Zhao, Jian, Longo, Nicola, Lewis, Robert G., Nicholas, Thomas J., Boyden, Steven E., Andrews, Ashley, Larson, Austin, Bayrak‐Toydemir, Pinar, Botto, Lorenzo D., and Mao, Rong

Abstract

The NFIX gene encodes a DNA‐binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall–Smith syndrome (MIM 602535), which are clinically distinct due to different disease‐causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N‐terminal DNA binding and dimerization domain or are protein‐truncating variants that trigger nonsense‐mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall–Smith syndrome are protein‐truncating and are clustered between exons 6 and 10, including a recurrent Alu‐mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall–Smith syndrome is likely due to a dominant‐negative effect of these protein‐truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon‐level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Diagnosis, Treatment, and Clinical Outcome of Patients with Mitochondrial Trifunctional Protein/Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency

Author

De Biase, Irene, Viau, Krista S., Liu, Aiping, Yuzyuk, Tatiana, Botto, Lorenzo D., Pasquali, Marzia, Longo, Nicola, Baumgartner, Matthias R., Series editor, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Peters, Verena, Series editor, Morava, Eva, Editor-in-chief, Zschocke, Johannes, Series editor, and Baumgartner, Matthias, editor

Published
2017
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17. The burden, prevention and care of infants and children with congenital anomalies in sub-Saharan Africa: A scoping review

Author

Leke, Aminkeng Zawuo, primary, Malherbe, Helen, additional, Kalk, Emma, additional, Mehta, Ushma, additional, Kisa, Phylis, additional, Botto, Lorenzo D., additional, Ayede, Idowu, additional, Fairlie, Lee, additional, Maboh, Nkwati Michel, additional, Orioli, Ieda, additional, Zash, Rebecca, additional, Kusolo, Ronald, additional, Mumpe-Mwanja, Daniel, additional, Serujogi, Robert, additional, Bongomin, Bodo, additional, Osoro, Caroline, additional, Dah, Clarisse, additional, Sentumbwe–Mugisha, Olive, additional, Shabani, Hamisi Kimaro, additional, Musoke, Philippa, additional, Dolk, Helen, additional, and Barlow-Mosha, Linda, additional

Published
2023
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25. Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences

Author

Wortmann, Saskia B., Chen, Margaret A., Colombo, Roberto, Pontoglio, Alessandro, Alhaddad, Bader, Botto, Lorenzo D., Yuzyuk, Tatiana, Coughlin, Curtis R., Descartes, Maria, Grűnewald, Stephanie, Maranda, Bruno, Mills, Philippa B., Pitt, James, Potente, Catherine, Rodenburg, Richard, Kluijtmans, Leo A. J., Sampath, Srirangan, Pai, Emil F., Wevers, Ron A., Tiller, George E., Wortmann, Saskia B., Wevers, Ron A., Tiller, George E., Chen, Margaret A., Colombo, Roberto, Pontoglio, Alessandro, Alhaddad, Bader, Botto, Lorenzo D., Yuzyuk, Tatiana, Coughlin, Curtis R., Descartes, Maria, Grűnewald, Stephanie, Kyriss, McKenna N. M., Maranda, Bruno, Mills, Philippa B., Pitt, James, Potente, Catherine, Reid, Emma S., Rodenburg, Richard, Kluijtmans, Leo A. J., Sampath, Srirangan, Thomas, Janet A., Waters, Paula J., White, Susan M., Pai, Emil F., and and additional individual contributors

Published
2017
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26. Does Maternal Exposure to Secondhand Tobacco Smoke During Pregnancy Increase the Risk for Preterm or Small-for-Gestational Age Birth?

Author

Hoyt, Adrienne T., Canfield, Mark A., Romitti, Paul A., Botto, Lorenzo D., Anderka, Marlene T., Krikov, Sergey V., and Feldkamp, Marcia L.

Subjects
Pregnancy complications -- Risk factors -- Research, Passive smoking -- Complications and side effects -- Research, Premature birth -- Risk factors -- Research, Health care industry
Abstract

Introduction While associations between active smoking and various adverse birth outcomes (ABOs) have been reported in the literature, less is known about the impact of secondhand smoke (SHS) on many pregnancy outcomes. Methods We examined the relationship between maternal exposure to SHS during pregnancy and preterm (< 37 weeks gestation) and small-for-gestational age (SGA; assessed using sex-, race/ethnic-, and parity-specific growth curves) singleton births using non-smoking controls from the National Birth Defects Prevention Study (1997-2011). Multivariable logistic regression models for household, workplace/school, and combined SHS exposure-controlled for maternal education, race/ethnicity, pre-pregnancy body mass index, and high blood pressure-were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Interaction was assessed for maternal folic acid supplementation, alcohol use, age at delivery, and infant sex. Results Infants of 8855 mothers were examined in the preterm birth analysis with 666 (7.5%) categorized as preterm, 574 moderately preterm (32-36 weeks), and 92 very preterm (< 32 weeks). For the SGA analysis, infants of 8684 mothers were examined with 670 (7.7%) categorized as SGA. The aORs for mothers reporting both household and workplace/school SHS were elevated for preterm (aOR 1.99; 95% CI 1.13-3.50) and moderately preterm birth (32-36 weeks) (aOR 2.17; 95% CI 1.22-3.88). No results for the SGA analysis achieved significance, nor was evidence of interaction evident. Conclusion The findings suggest an association between SHS from multiple exposure sources and preterm birth, but no evidence for association with SGA births. Continued study of SHS and ABOs is needed to best inform public health prevention programs., Author(s): Adrienne T. Hoyt [sup.1] , Mark A. Canfield [sup.1] , Paul A. Romitti [sup.2] , Lorenzo D. Botto [sup.3] , Marlene T. Anderka [sup.4] , Sergey V. Krikov [sup.3] [...]

Published
2018
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30. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy

Author

Genetica Klinische Genetica, Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, Escayg, Andrew, Genetica Klinische Genetica, Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, and Escayg, Andrew

Published
2023

31. ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy

Author

Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Angel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van der Zwaag, Bert, Aleck, Kyrieckos A, Fazenbaker, Andrew C, Balciuniene, Jorune, Dubbs, Holly A, Marsh, Eric D, Garber, Kathryn, Ek, Jakob, Duno, Morten, Hoei-Hansen, Christina E, Deardorff, Matthew A, Raca, Gordana, Quindipan, Catherine, Van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjorg, Moller, Rikke S, Whitney, Andrea, Douglas, Andrew GL, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argilli, Emanuela, Sherr, Elliot H, Dobyns, William B, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, and Escayg, Andrew

Subjects
neurodevelopmental disorders, ATP6V0C, VMA3, V-ATPase, Neurology (clinical), epilepsy genetics
Abstract

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms. ispartof: BRAIN vol:146 issue:4 ispartof: location:England status: Published online

Published
2023

38. Mandatory food fortification with folic acid – Authors' reply

Author

Kancherla, Vijaya, primary, Botto, Lorenzo D, additional, Rowe, Laura A, additional, Shlobin, Nathan A, additional, Caceres, Adrian, additional, Arynchyna-Smith, Anastasia, additional, Zimmerman, Kathrin, additional, Blount, Jeffrey, additional, Kibruyisfaw, Zewdie, additional, Ghotme, Kemel A, additional, Karmarkar, Santosh, additional, Fieggen, Graham, additional, Roozen, Sylvia, additional, Oakley, Godfrey P, additional, Rosseau, Gail, additional, and Berry, Robert J, additional

Published
2022
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39. Health Care Usage Among Adolescents With Congenital Heart Defects at 5 Sites in the United States, 2011 to 2013

Author

Lui, George K., primary, Sommerhalter, Kristin, additional, Xi, Yizhao, additional, Botto, Lorenzo D., additional, Crume, Tessa, additional, Farr, Sherry, additional, Feldkamp, Marcia L., additional, Glidewell, Jill, additional, Hsu, Daphne, additional, Khanna, Amber, additional, Krikov, Sergey, additional, Li, Jennifer, additional, Raskind‐Hood, Cheryl, additional, Sarno, Lauren, additional, Van Zutphen, Alissa R., additional, Zaidi, Ali, additional, Soim, Aida, additional, and Book, Wendy M., additional

Published
2022
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40. Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway

Author

Sokoya, Tolulope, primary, Parolek, Jan, primary, Foged, Mads Møller, additional, Danylchuk, Dmytro I, additional, Bozan, Manuel, additional, Sarkar, Bingshati, additional, Hilderink, Angelika, additional, Philippi, Michael, additional, Botto, Lorenzo D, additional, Terhal, Paulien A, additional, Mäkitie, Outi, additional, Piehler, Jacob, additional, Kim, Yeongho, additional, Burd, Christopher G, additional, Klymchenko, Andrey S, additional, Maeda, Kenji, additional, and Holthuis, Joost CM, additional

Published
2022
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41. Author response: Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway

Author

Sokoya, Tolulope, primary, Parolek, Jan, primary, Foged, Mads Møller, additional, Danylchuk, Dmytro I, additional, Bozan, Manuel, additional, Sarkar, Bingshati, additional, Hilderink, Angelika, additional, Philippi, Michael, additional, Botto, Lorenzo D, additional, Terhal, Paulien A, additional, Mäkitie, Outi, additional, Piehler, Jacob, additional, Kim, Yeongho, additional, Burd, Christopher G, additional, Klymchenko, Andrey S, additional, Maeda, Kenji, additional, and Holthuis, Joost CM, additional

Published
2022
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42. ATP6V0C variants impair vacuolar V-ATPase causing a neurodevelopmental disorder often associated with epilepsy

Author

Mattison, Kari A, Tossing, Gilles, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, McCann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, Escayg, Andrew, Mattison, Kari A, Tossing, Gille, Mulroe, Fred, Simmons, Callum, Butler, Kameryn M, Schreiber, Alison, Alsadah, Adnan, Neilson, Derek E, Naess, Karin, Wedell, Anna, Wredenberg, Anna, Sorlin, Arthur, Mccann, Emma, Burghel, George J, Menendez, Beatriz, Hoganson, George E, Botto, Lorenzo D, Filloux, Francis M, Aledo-Serrano, Ángel, Gil-Nagel, Antonio, Tatton-Brown, Katrina, Verbeek, Nienke E, van Hirtum-Das, Michele, Breckpot, Jeroen, Hammer, Trine Bjørg, Møller, Rikke S, Whitney, Andrea, Douglas, Andrew G L, Kharbanda, Mira, Brunetti-Pierri, Nicola, Morleo, Manuela, Nigro, Vincenzo, May, Halie J, Tao, James X, Argili, Emanuela, Sherr, Elliot H, Dobyns, William B, Consortium, Genomics England Research, Baines, Richard A, Warwicker, Jim, Parker, J Alex, Banka, Siddharth, Campeau, Philippe M, and Escayg, Andrew

Subjects
neurodevelopmental disorders, ATP6V0C, VMA3, epilepsy genetic, V-ATPase
Abstract

The vacuolar H+-ATPase (V-ATPase) is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the V-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modeling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased V-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behavior, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction, and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder, and provides insight into disease mechanisms.

Published
2022

45. Join World Birth Defects Day

Author

Groisman, Boris, Bermejo-Sánchez, Eva, Romitti, Paul A., Botto, Lorenzo D., Feldkamp, Marcia L., Walani, Salimah R., and Mastroiacovo, Pierpaolo

Published
2019
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47. HeterozygousNOTCH1Variants Cause CNS Immune Activation and Microangiopathy

Author

Helman, Guy, primary, Zarekiani, Parand, additional, Tromp, Samantha A.M., additional, Andrews, Ashley, additional, Botto, Lorenzo D., additional, Bonkowsky, Joshua L., additional, Chassevent, Anna, additional, Giorgio, Elisa, additional, Pippucci, Tommaso, additional, Wei, Shen, additional, Smith‐Hicks, Constance, additional, Vaula, Giovanna, additional, Willemsen, Michèl A.A.P, additional, Schimmel, Mareike, additional, Vollert, Kurt, additional, Shimizu, Fumitaka, additional, Kanda, Takashi, additional, Lynch, Matthew, additional, Roscioli, Tony, additional, Taft, Ryan J., additional, Simons, Cas, additional, Bugiani, Marianna, additional, Kuijpers, Taco W., additional, and van der Knaap, Marjo S., additional

Published
2022
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