350 results on '"Gleeson JG"'
Search Results
2. Translational benefits to patients in the post-genomic era
- Author
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Gleeson, JG
- Published
- 2012
3. A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex
- Author
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Antaki, D, primary, Maihofer, A, additional, Klein, M, additional, Guevara, J, additional, Grove, J, additional, Carey, Caitlin, additional, Hong, O, additional, Arranz, MJ, additional, Hervas, A, additional, Corsello, C, additional, Muotri, AR, additional, Iakoucheva, LM, additional, Courchesne, E, additional, Pierce, K, additional, Gleeson, JG, additional, Robinson, E, additional, Nievergelt, CM, additional, and Sebat, J, additional
- Published
- 2021
- Full Text
- View/download PDF
4. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects
- Author
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Manole, A, Efthymiou, S, O'Connor, E, Mendes, MI, Jennings, M, Maroofian, R, Davagnanam, I, Mankad, K, Lopez, MR, Salpietro, V, Harripaul, R, Badalato, L, Walia, J, Francklyn, CS, Athanasiou-Fragkouli, A, Sullivan, R, Desai, S, Baranano, K, Zafar, F, Rana, N, Ilyas, M, Horga, A, Kara, M, Mattioli, F, Goldenberg, A, Griffin, H, Piton, A, Henderson, LB, Kara, B, Aslanger, AD, Raaphorst, J, Pfundt, R, Portier, R, Shinawi, M, Kirby, A, Christensen, KM, Wang, L, Rosti, RO, Paracha, SA, Sarwar, MT, Jenkins, D, SYNAPS Study Group, Ahmed, J, Santoni, FA, Ranza, E, Iwaszkiewicz, J, Cytrynbaum, C, Weksberg, R, Wentzensen, IM, Guillen Sacoto, MJ, Si, Y, Telegrafi, A, Andrews, MV, Baldridge, D, Gabriel, H, Mohr, J, Oehl-Jaschkowitz, B, Debard, S, Senger, B, Fischer, F, van Ravenwaaij, C, Fock, AJM, Stevens, SJC, Bähler, J, Nasar, A, Mantovani, JF, Manzur, A, Sarkozy, A, Smith, DEC, Salomons, GS, Ahmed, ZM, Riazuddin, S, Usmani, MA, Seibt, A, Ansar, M, Antonarakis, SE, Vincent, JB, Ayub, M, Grimmel, M, Jelsig, AM, Hjortshøj, TD, Karstensen, HG, Hummel, M, Haack, TB, Jamshidi, Y, Distelmaier, F, Horvath, R, Gleeson, JG, Becker, H, Mandel, J-L, Koolen, DA, and Houlden, H
- Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
- Published
- 2020
5. Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network
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Mcconnell, Mj, Moran, Jv, Abyzov, A, Akbarian, S, Bae, T, Cortes-Ciriano, I, Erwin, Ja, Fasching, L, Flasch, Da, Freed, D, Ganz, J, Jaffe, Ae, Kwan, Ky, Kwon, M, Lodato, Ma, Mills, Re, Paquola, Acm, Rodin, Re, Rosenbluh, C, Sestan, N, Sherman, Ma, Shin, Jh, Song, S, Straub, Re, Thorpe, J, Weinberger, Dr, Urban, Ae, Zhou, B, Gage, Fh, Lehner, T, Senthil, G, Walsh, Ca, Chess, A, Courchesne, E, Gleeson, Jg, Kidd, Jm, Park, Pj, Pevsner, J, Vaccarino, Fm, Barton, Ar, Bekiranov, S, Bohrson, Cl, Burbulis, Ie, Chronister, W, Coppola, G, Daily, K, D'Gama, Am, Emery, Sb, Frisbie, Tj, Gao, T, Gulyás-Kovács, A, Haakenson, M, Keil, Jm, Kopera, Hc, Lam, Mm, Lee, Ea, Marques-Bonet, T, Mathern, Gw, Moldovan, Jb, Oetjens, Mt, Omberg, L, Peters, Ma, Pochareddy, S, Pramparo, T, Ratan, A, Sanavia, T, Shi, L, Skarica, M, Wang, J, Wang, M, Wang, Y, Wierman, M, Wolpert, M, Woodworth, M, Zhao, X, and Zhou, W
- Subjects
DNA Replication ,0301 basic medicine ,DNA Repair ,Brain Somatic Mosaicism ,Somatic cell ,DNA Mutational Analysis ,Genomics ,Disease ,Biology ,Article ,Germline ,03 medical and health sciences ,Neural Stem Cells ,Humans ,Copy-number variation ,Neurons ,Genetics ,Multidisciplinary ,Genome, Human ,Mosaicism ,Mental Disorders ,Brain ,Phenotype ,Germ Cells ,030104 developmental biology ,Human genome ,Nerve Net ,Nervous System Diseases ,Cell Division ,Neurotypical ,DNA Damage - Abstract
BACKGROUND Elucidating the genetic architecture of neuropsychiatric disorders remains a major scientific and medical challenge. Emerging genomic technologies now permit the analysis of somatic mosaicism in human tissues. The measured frequencies of single-nucleotide variants (SNVs), small insertion/deletion (indel) mutations, structural variants [including copy number variants (CNVs), inversions, translocations, and whole-chromosome gains or losses], and mobile genetic element insertions (MEIs) indicate that each neuron may harbor hundreds of somatic mutations. Given the long life span of neurons and their central role in neural circuits and behavior, somatic mosaicism represents a potential mechanism that may contribute to neuronal diversity and the etiology of numerous neuropsychiatric disorders. ADVANCES Somatic mutations that confer cellular proliferative or cellular survival phenotypes have been identified in patients with cortical malformations. These data have led to the hypothesis that somatic mutations may also confer phenotypes to subsets of neurons, which could increase the risk of developing certain neuropsychiatric disorders. Genomic technologies, including advances in long-read, next-generation DNA sequencing technologies, single-cell genomics, and cutting-edge bioinformatics, can now make it possible to determine the types and frequencies of somatic mutations within the human brain. However, a comprehensive understanding of the contribution of somatic mosaicism to neurotypical brain development and neuropsychiatric disease requires a coordinated, multi-institutional effort. The National Institute of Mental Health (NIMH) has formed a network of 18 investigative teams representing 15 institutions called the Brain Somatic Mosaicism Network (BSMN). Each research team will use an array of genomic technologies to exploit well-curated human tissue repositories in an effort to define the frequency and pattern of somatic mutations in neurotypical individuals and in schizophrenia, autism spectrum disorder, bipolar disorder, Tourette syndrome, and epilepsy patient populations. Collectively, these efforts are estimated to generate a community resource of more than 10,000 DNA-sequencing data sets and will enable a cross-platform integrated analysis with other NIMH initiatives, such as the PsychENCODE project and the CommonMind Consortium. OUTLOOK A fundamental open question in neurodevelopmental genetics is whether and how somatic mosaicism may contribute to neuronal diversity within the neurotypical spectrum and in diseased brains. Healthy individuals may harbor known pathogenic somatic mutations at subclinical frequencies, and the local composition of neural cell types may be altered by mutations conferring prosurvival phenotypes in subsets of neurons. By extension, the neurotypical architecture of somatic mutations may confer circuit-level differences that would not be present if every neuron had an identical genome. Given the apparent abundance of somatic mutations within neurons, an in-depth understanding of how different types of somatic mosaicism affect neural function could yield mechanistic insight into the etiology of neurodevelopmental and neuropsychiatric disorders. The BSMN will examine large collections of postmortem brain tissue from neurotypical individuals and patients with neuropsychiatric disorders. By sequencing brain DNA and single neuronal genomes directly, rather than genomic DNA derived from peripheral blood or other somatic tissues, the BSMN will test the hypothesis that brain somatic variants contribute to neuropsychiatric disease. Notably, it is also possible that some inherited germline variants confer susceptibility to disease, which is later exacerbated by somatic mutations. Confirming such a scenario could increase our understanding of the genetic risk architecture of neuropsychiatric disease and may, in part, explain discordant neuropsychiatric phenotypes between identical twins. Results from these studies may lead to the discovery of biomarkers and genetic targets to improve the treatment of neuropsychiatric disease and may offer hope for improving the lives of patients and their families.
- Published
- 2017
6. An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes
- Author
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Wheway, G, Schmidts, M, Mans, DA, Szymanska, K, Nguyen, TT, Racher, H, Phelps, IG, Toedt, G, Kennedy, J, Wunderlich, KA, Sorusch, N, Abdelhamed, ZA, Natarajan, S, Herridge, W, van Reeuwijk, J, Horn, N, Boldt, K, Parry, DA, Letteboer, SJ, Roosing, S, Adams, M, Bell, SM, Bond, J, Higgins, J, Morrison, EE, Tomlinson, DC, Slaats, GG, van Dam, TJ, Huang, L, Kessler, K, Giessl, A, Logan, CV, Boyle, EA, Shendure, J, Anazi, S, Aldahmesh, M, Al Hazzaa, S, Hegele, RA, Ober, C, Frosk, P, Mhanni, AA, Chodirker, BN, Chudley, AE, Lamont, R, Bernier, FP, Beaulieu, CL, Gordon, P, Pon, RT, Donahue, C, Barkovich, AJ, Wolf, L, Toomes, C, Thiel, CT, Boycott, KM, McKibbin, M, Inglehearn, CF, UK10K Consortium, University ofWashington Center forMendelian Genomics, Stewart, F, Omran, H, Huynen, MA, Sergouniotis, PI, Alkuraya, FS, Parboosingh, JS, Innes, AM, Willoughby, CE, Giles, RH, Webster, AR, Ueffing, M, Blacque, O, Gleeson, JG, Wolfrum, U, Beales, PL, Gibson, T, Doherty, D, Mitchison, HM, Roepman, R, and Johnson, CA
- Abstract
Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.
- Published
- 2015
7. CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium
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Lee JE, Silhavy JL, Zaki MS, Schroth J, Bielas SL, Marsh SE, Olvera J, Brancati F, Iannicelli M, Ikegami K, Schlossman AM, Merriman B, Attixe9-Bitach T, Logan CV, Glass IA, Cluckey A, Louie CM, Lee JH, Raynes HR, Rapin I, Setou M, Barbot C, Boltshauser E, Nelson SF, Hildebrandt F, Johnson CA, Doherty DA, Valente EM, and Gleeson JG.
- Published
- 2012
8. TSGA14 is mutated in Joubert syndrome ans is required for tubulin glutamylation at the cilium
- Author
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Lee, Je, Silhavy, Jl, Zaki, Ms, Schroth, J, Bielas, Sl, Marsh, Se, Olvera, J, Brancati, F, Iannicelli, M, Ikegami, K, Schlossman, Am, Merriman, B, Attié Bitach, T, Logan, Cv, Glass, Ia, Cluckey, A, Louie, Cm, Lee, Jh, Raynes, Hr, Rapin, I, Setou, M, Barbot, C, Boltshauser, E, Nelson, Sf, Hildebrandt, F, Johnson, Ca, Doherty, Da, Valente, Enza Maria, and Gleeson, Jg
- Published
- 2012
9. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders
- Author
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Brancati, F, Travaglini, L, Zablocka, D, Boltshauser, E, Accorsi, P, Montagna, G, Silhavy, Jl, Barrano, G, Bertini, E, Emma, F, Rigoli, L, Dallapiccola, B, Gleeson, Jg, and Valente, Em
- Published
- 2008
10. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome
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Cantagrel, V, Silhavy, Jl, Bielas, S, Swistun, D, Marsh, Se, Bertrand, J, Audollent, S, Attié Bitach, T, Holden, Kr, Dobyns, Wb, Traver, D, Al Gazali, L, Ali, Br, Lindner, Th, Caspary, T, Otto, Ea, Hildebrandt, F, Glass, Ia, Logan, Cv, Johnson, Ca, Bennett, C, Brancati, F, Grattan Smith, P, Leventer, J, Van Coster, R, Dias, K, Moco, C, Moreira, Ae Kim, C, Akiss, A, Maegawa, G, Abdel Salam GMH, Abdel Aleem, A, Zaki, Ms, Marti, I, Quijano Roy, S, de Lonlay, P, Verloes A, A., Touraine, R, Koenig, M, Lagier Tourenne, C, Messer, J, Philippi, H, Tzeli, Sk, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Magee, A, Stuart, B, Lev, D, Michelson, M, Ben Zeev, B, Fischetto, R, Gentile, M, Battaglia, Giordano, L, Boccone, L, Ruggieri, M, Bigoni, S, Ferlini, A, Donati, Ma, Procopio, E, Lapi, E, Genuardi, M, Caridi, G, Faravelli, F, Ghiggeri, G, Briuglia, Silvana, Tortorella, Gaetano, Rigoli, Luciana Concetta, SALPIETRO DAMIANO, Carmelo, D’Arrigo, S, Pantaleoni, C, Riva, D, Uziel, G, Laverda, Am, Permunian, A, Bova, S, Fazz, Ei, Sabrina, S, Battini, R, Bertini, E, Dallapiccola, B, Cilio, Mr, Di Sabato, M, Emma, F, Leuzzi, V, Parisi, P, Simonati, A, Al Tawari AA, Bastaki, L, Ahmad Aqueel, A, Jong, Mm, Koul, R, Rajab, A, Sztriha, L, Azam, M, Barbot, C, Rodriguez, B, Pascual Castroviejo, I, Eugen Boltshauser, E, Hulya, H, Comu, S, Akcakus, M, Sahin, Y, Phadke, Sr, Melick, N, Mikati, M, Nicholl, D, Hurst, J, Hennekam, Rcm, Bernes, S, Sanchez, H, Clark, Ae, Wynshaw Boris, A, Donahue, C, Sherr, Eh, Barkovich, Aj, Hahn, D., Sanger, Td, Gallager, Te, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Walsh CA, Soul, Jmckanna, T, Joanne Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Amy Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Cruse, Rp, Lotzete, Swoboda, Kj, Viskochil, Dh, Valente, Em, Woods, Cg, and Gleeson, Jg
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Cerebellum ,Ataxia ,TMEM67 ,Molecular Sequence Data ,Biology ,Joubert Syndrome ,Joubert syndrome ,Article ,cilia gene ARL13B ,mutation ,03 medical and health sciences ,0302 clinical medicine ,Ciliogenesis ,INPP5E ,medicine ,Genetics ,Animals ,Humans ,Genetics(clinical) ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Cilia ,Genetics (clinical) ,Conserved Sequence ,Zebrafish ,030304 developmental biology ,Neurons ,0303 health sciences ,Brain Diseases ,ADP-Ribosylation Factors ,Cilium ,Chromosome Mapping ,Computational Biology ,Syndrome ,Mutation ,medicine.disease ,Cell biology ,medicine.anatomical_structure ,RPGRIP1L ,medicine.symptom ,Abnormalities ,Multiple ,030217 neurology & neurosurgery - Abstract
Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the “molar tooth sign” on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.
- Published
- 2008
11. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders
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Brancati, F, Barrano, G, Silhavy, Jl, Marsh, Se, Travaglini, L, Bielas, Sl, Amorini, M, Zablocka, D, Kayserili, H, Al Gazali, L, Bertini, E, Boltshauser, E, D'Hooghe, M, Fazzi, E, Fenerci, Ey, Hennekam, Rc, Kiss, A, Lees, Mm, Marco, E, Phadke, Sr, Rigoli, L, Romano, S, Salpietro, Cd, Sherr, Eh, Signorini, S, Stromme, P, Stuart, B, Sztriha, L, Viskochil, Dh, Yuksel, A, Dallapiccola, [International JSRD Study Group], Valente, Em, Gleeson, Jg, Smith, P, Leventer, R, Janecke, A, Van Coster, R, Dias, K, Moco, C, Moreira, A, Chong, Ak, Maegawa, G, Abdel Salam GMH, Abdel Aleem, A, Zaki, Ms, Martu, I, Quijano Roy, S, De Lonlay, P, Verloes, A, Touraine, R, Koenig, M, Lagier Tourenne, C, Messer, J, Philippi, H, Tzeli, Sk, Halldorsson, S, Johannsdotir, J, Ludvigsson, P, Magee, A, Lev, D, Michelson, M, Ben Zev, B, Fischetto, R, Gentile, M, Battaglia, S, Giordano, L, Boccone, L, Ruggieri, Martino, Bigoni, S, Ferlini, A, Donati, Ma, Procopio, E, Cardidi, G, Faravelli, F, Ghiggeri, G, Briuglia, S, Tortorella, G, D’Arrigo, S, Pantaleoni, C, Riva, D, Uziel, G, Lavercla, Am, Permunian, A, Bova, S, Battini, R, Cilio, Mr, Di Sabato, M, Emma, F, Leuzzi, V, Parisi, P, Simonati, A, Al Tawari AA, Bastaki, L, Aqeel, A, De Jong MM, Koul, R, Rajab, A, Azam, M, Barbot, C, Rodriguez, B, Pascual Castroviejo, I, Comu, S, Akcakus, M, Nicholl, D, Woods, Cg, Bennet, C, Hurst, J, Walsh, Ca, Bernes, S, Sanchez, H, Clark, Ae, Donahue, C, Hahn, J, Sanger, Td, Gallager, Te, Dobyns, Wb, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Mckanna, T, Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Holden, K, Cruse, Rp, and Swoboda, Kj
- Published
- 2007
12. AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders
- Author
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Valente, Em, Brancati, F, Silhavy, Jl, Castori, M, Marsh, Se, Barrano, G, Bertini, E, Boltshauser, E, Zaki, Ms, Abdel Aleem, A, Abdel Salam GM, Bellacchio, E, Battini, R, Cruse, Rp, Dobyns, Wb, Krishnamoorthy, Ks, Lagier Tourenne, C, Magee, A, Pascual Castroviejo, I, SALPIETRO DAMIANO, Carmelo, Sarco, D, Richard, Leventer, Padraic Grattan Smith, Andreas, Janecke, Marc, D’Hooghe, Rudy Van Coster, Karin, Dias, Carla, Moco, Ana, Moreira, Chong Ae Kim, Gustavo, Maegawa, Itxaso, Marti, Susana Quijano Roy, Alain, Verloes, Renaud, Touraine, Miche, Bernard, Stuart, Dorit, Lev, Bruria Ben Zeev, Rita, Fischetto, Mattia, Gentile, Lucio, Giordano, Loredana, Boccone, Martino, Ruggieri, Stefania, Bigoni, Maria Alide Donati, Elena, Procopio, Gianluca, Caridi, Francesca, Faravelli, Gianmarco, Ghiggeri, Briuglia, Silvana, Gaetano, Tortorella, Stefano, D’Arrigo, Chiara, Pantaleoni, Daria, Riva, Graziella, Uziel, Stefania, Bova, Elisa, Fazzi, Sabrina, Signorini, Maria Roberta Cilio, Marilu` Di Sabato, Francesco, Emma, Vincenzo, Leuzzi, Pasquale, Parisi, Alessandro, Simonati, de Jong, Mirjam M., Matloob, Azam, Berta, Rodriguez, Hulya, Kayserili, Lihadh Al Gazali, Laszlo, Sztriha, David, Nicholl, Geoffrey Woods, C., Raoul, Hennekam, Saunder, Bernes, Henry, Sanchez, Clark, Aldon E., Elysa, Demarco, Clement, Donahue, Elliot, Sherr, Jin, Hahn, Terence, D, Sanger, Gallager H, Tomas E., Cynthia, Daugherty, Walsh, Christopher A., Trudy, Mckanna, Joanne, Milisa, Chung, Wendy K., De Vivo, Darryl C., Hillary, Raynes, Romaine, Schubert, Alison, Seward, Brooks, David G., Amy, Goldstein, James, Caldwell, Eco, Finsecke, Kenton, Holden, Swobod, Kathryn J., Dave Viskochil, Dallapiccola, B, and Gleeson, Jg
- Subjects
Male ,Models, Molecular ,Developmental Disabilities ,DNA Mutational Analysis ,Chromosome Disorders ,Gene mutation ,medicine.disease_cause ,Gene Frequency ,Models ,Missense mutation ,Adaptor Proteins, Signal Transducing ,Adolescent ,Adult ,Animals ,Brain Diseases ,Brain Stem ,Child ,Child, Preschool ,Family Health ,Female ,Humans ,Infant ,Magnetic Resonance Imaging ,Polymorphism, Genetic ,Mutation ,Neuroscience (all) ,Genetics ,Adaptor Proteins ,Joubert syndrome ,Joubert Syndrome Related Disorders ,AHI1 gene ,mutation ,Neurology ,Consanguinity ,Biology ,Genetic ,medicine ,Polymorphism ,Preschool ,Gene ,Allele frequency ,Signal Transducing ,Molecular ,medicine.disease ,Adaptor Proteins, Vesicular Transport ,Cerebellar vermis ,Neurology (clinical) - Abstract
Author(s): Valente, E M; Brancat, F; Silhavy, J L; Castori, M; March, S E; Barrano, G; Bertini, E; Boltshauser, E; Zaki, M S; Abdel-Aleem, A; Abdel-Salam, GMH; Bellacchlo, E; Battini, R; Cruse, R P; Dobyns, W B; Krishnamoorthy, K S; Lagier-Tourenne, C; Magee, A; Pascual-Castroviejo, I; Salpietro, C D; Sarco, D; Dallapiccola, B; Gleeson, J G | Abstract: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. Methods: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. Results: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. Interpretation AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.
- Published
- 2006
13. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome
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Valente, Enza Maria, Silhavy, Jl, Brancati, F, Barrano, G, Krishnaswami, Sr, Castori, M, Lancaster, Ma, Boltshauser, E, Boccone, L, AL GAZALI, L, Fazzi, E, Signorini, S, Louie, Cm, Bellacchio, E, Bertini, E, Dallapiccola, B, and Gleeson, Jg
- Published
- 2006
14. Mutations in the CEP290 gene, encoding a centrosomal protein, cause pleiotropic forms of Joubert Syndrome
- Author
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Valente, Em, Silhavy, Jl, Brancati, F., Barrano, G, Krishnaswami, Sr, Castori, M, Lancaster, Ma, Boltshauser, E, Boccone, L, AL-GAZALI, L, Fazzi, E, Signorini, S, Louie, Cm, Bellacchio, E, Bertini, E, DALLA PICCOLA, B, and Gleeson, Jg
- Published
- 2006
15. The ciliary proteins Meckelin and Jouberin are required for retinoic acid-dependent neural differentiation of mouse embryonic stem cells
- Author
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Romani, S, primary, Illi, B, additional, De Mori, R, additional, Gleeson, JG, additional, and Valente, EM, additional
- Published
- 2012
- Full Text
- View/download PDF
16. Diencephalic-mesencephalic junction dysplasia: a novel recessive brain malformation.
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Zaki MS, Saleem SN, Dobyns WB, Barkovich AJ, Bartsch H, Dale AM, Ashtari M, Akizu N, Gleeson JG, Grijalvo-Perez AM, Zaki, Maha S, Saleem, Sahar N, Dobyns, William B, Barkovich, A James, Bartsch, Hauke, Dale, Anders M, Ashtari, Manzar, Akizu, Naiara, Gleeson, Joseph G, and Grijalvo-Perez, Ana Maria
- Abstract
We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic-mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic-mesencephalic junction with a characteristic 'butterfly'-like contour of the midbrain on axial sections. Additional imaging features included variable degrees of supratentorial ventricular dilatation and hypoplasia to complete agenesis of the corpus callosum. Diffusion tensor imaging showed diffuse hypomyelination and lack of an identifiable corticospinal tract. All patients displayed severe cognitive impairment, post-natal progressive microcephaly, axial hypotonia, spastic quadriparesis and seizures. Autistic features were noted in older cases. Talipes equinovarus, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous were additional findings in two families. One of the patients required shunting for hydrocephalus; however, this yielded no change in ventricular size suggestive of dysplasia rather than obstruction. We propose the term 'diencephalic-mesencephalic junction dysplasia' to characterize this autosomal recessive malformation. [ABSTRACT FROM AUTHOR]
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- 2012
- Full Text
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17. Distinguishing 3 classes of corpus callosal abnormalities in consanguineous families.
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Hanna RM, Marsh SE, Swistun D, Al-Gazali L, Zaki MS, Abdel-Salam GM, Al-Tawari A, Bastaki L, Kayserili H, Rajab A, Boglárka B, Dietrich RB, Dobyns WB, Truwit CL, Sattar S, Chuang NA, Sherr EH, Gleeson JG, Hanna, R M, and Marsh, S E
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- 2011
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18. Distinguishing the four genetic causes of Jouberts syndrome-related disorders.
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Valente EM, Marsh SE, Castori M, Dixon-Salazar T, Bertini E, Al-Gazali L, Messer J, Barbot C, Woods CG, Boltshauser E, Al-Tawari AA, Salpietro CD, Kayserili H, Sztriha L, Gribaa M, Koenig M, Dallapiccola B, and Gleeson JG
- Published
- 2005
19. Mild paroxysmal kinesigenic dyskinesia caused by PRRT2 missense mutation with reduced penetrance.
- Author
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Friedman J, Olvera J, Silhavy JL, Gabriel SB, Gleeson JG, Friedman, Jennifer, Olvera, Jesus, Silhavy, Jennifer L, Gabriel, Stacey B, and Gleeson, Joseph G
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- 2012
- Full Text
- View/download PDF
20. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies
- Author
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S. Kitsiou Tzeli, Hülya Kayserili, L. Giordano, B. Rodriguez, P. Collignon, V. Sabolic Avramovska, Silvana Briuglia, Christopher A. Walsh, Laila Bastaki, Amy Goldstein, Francesca Faravelli, F. Papadia, A. Permunian, Alessandro Simonati, S. Halldorsson, Gian Marco Ghiggeri, David G. Brooks, Clara Barbot, Kathryn J. Swoboda, Chiara Pantaleoni, O. D'Addato, Jason W. Caldwell, Maria Roberta Cilio, Soumaya Mougou-Zerelli, M. Vascotto, Andreas Zankl, Gaetano Tortorella, Julia Tantau, Elliott H. Sherr, Patrizia Accorsi, Maurizio Genuardi, Carmelo Salpietro, G. Marra, Pierangela Castorina, Petter Strømme, J. Johannsdottir, Bruno Dallapiccola, Kenton R. Holden, Donatella Greco, Maria Spanò, Pasquale Parisi, Roberta Battini, Paola Grammatico, P. Ludvigsson, Dorit Lev, Daria Riva, C. Ae Kim, WB Dobyns, L. Martorell Sampol, Robert P. Cruse, H. Raynes, Sabrina Signorini, A. Seward, Raoul C.M. Hennekam, Elena Andreucci, Manuela Priolo, Banu Anlar, Bernard Stuart, Christopher P. Bennett, S. Comu, Christopher Geoffrey Woods, Vlatka Mejaški-Bošnjak, J. Milisa, Eamonn Sheridan, Melissa Lees, C. Moco, Ender Karaca, Miriam Iannicelli, Annalisa Mazzotta, C. Dacou-Voutetakis, Tania Attié-Bitach, Philippe Loget, D. Petkovic, L. Demerleir, Loredana Boccone, Meriem Tazir, Kalpathy S. Krishnamoorthy, Damir Lončarević, Dominika Swistun, Yves Sznajer, Stefano D'Arrigo, Ginevra Zanni, Angela Barnicoat, Marina Michelson, L. I. Al Gazali, Vincenzo Leuzzi, G. Uziel, A. Adami, B. Gener Querol, V. Udani, M. Di Giacomo, Maryse Bonnière, Enrico Bertini, K. Dias, Edward Blair, Johannes M. Penzien, M. Cazzagon, Susana Quijano-Roy, Trine Prescott, Barbara Scelsa, Giuseppina Vitiello, Francesco Brancati, Gilda Stringini, Trudy McKanna, Roser Pons, Renato Borgatti, M. Gentile, Dean Sarco, C. Von Der Lippe, Eugen Boltshauser, Luigina Spaccini, A. Pessagno, Alex Magee, Marilena Briguglio, Margherita Silengo, Lena Starck, M. L. Di Sabato, Roshan Koul, Nicole I. Wolf, A. M. Laverda, Elizabeth Flori, Clotilde Lagier-Tourenne, A. Matuleviciene, Matloob Azam, Kathrin Ludwig, Ghada M H Abdel-Salam, Atıl Yüksel, Johannes R. Lemke, Stefania Bigoni, Elizabeth Said, Anna Rajab, Mary Kay Koenig, Andreas R. Janecke, Asma A. Al-Tawari, Agnese Suppiej, Henry Sanchez, Wendy K. Chung, P. Guanciali, Heike Philippi, Silvia Majore, E. DeMarco, J. Hahn, Gianluca Caridi, Marc D'Hooghe, M. M. De Jong, M. Akcakus, Franco Stanzial, Silvia Battaglia, Gian Luigi Ardissino, Giangennaro Coppola, Jane A. Hurst, Terry D. Sanger, Alessandra Renieri, Nadia Elkhartoufi, Rita Fischetto, Alex E. Clark, S. Strozzi, S. Romano, Alain Verloes, Marzia Pollazzon, Elisa Fazzi, L. Yates, Faustina Lalatta, Sabine Sigaudy, Alessandra D'Amico, Brigitte Leroy, Joel Victor Fluss, David Viskochil, Alice Abdel-Aleem, Darryl C. De Vivo, Padraic Grattan-Smith, Corrado Romano, D. Nicholl, Regine Schubert, A. Moreira, Claudia Izzi, Barbara Gentilin, Gustavo Maegawa, Céline Gomes, László Sztriha, C. Donahue, Luciana Rigoli, Jean Messer, Sophie Thomas, E. Del Giudice, R. Van Coster, André Mégarbané, Ignacio Pascual-Castroviejo, Alessandra Ferlini, Topcu, R. Touraine, Ginevra Guanti, Lorena Travaglini, L. Ali Pacha, R. De Vescovi, Enza Maria Valente, Filippo Bernardi, L. Carr, Shubha R. Phadke, S. Bernes, Maria Teresa Divizia, C. Daugherty, M. Akgul, C. Macaluso, Maha S. Zaki, E. Finsecke, Itxaso Marti, Lorenzo Pinelli, F. McKay, Maria Amorini, Joseph G. Gleeson, F. Benedicenti, Bruria Ben-Zeev, Carla Uggetti, R. Romoli, Richard J. Leventer, Francesco Emma, T. E. Gallager, P. De Lonlay, Marco Seri, Bernard L. Maria, M.A. Donati, Bosanka Jocic-Jakubi, IANNICELLI M, BRANCATI F, MOUGOU-ZERELLI S, MAZZOTTA A, THOMAS S, ELKHARTOUFI N, TRAVAGLINI L, GOMES C, ARDISSINO GL, BERTINI E, BOLTSHAUSER E, CASTORINA P, D'ARRIGO S, FISCHETTO R, LEROY B, LOGET P, BONNIÈRE M, STARCK L, TANTAU J, GENTILIN B, MAJORE S, SWISTUN D, FLORI E, LALATTA F, PANTALEONI C, PENZIEN J, GRAMMATICO P, INTERNATIONAL JSRD STUDY GROUP, DALLAPICCOLA B, GLEESON JG, ATTIE-BITACH T, VALENTE EM. COLLABORATORS: ALI PACHA L, TAZIR M, ZANKL A, LEVENTER R, GRATTAN-SMITH P, JANECKE A, D'HOOGHE M, SZNAJER Y, VAN COSTER R, DEMERLEIR L, DIAS K, MOCO C, MOREIRA A, AE KIM C, MAEGAWA G, LONCAREVIC D, MEJASKI-BOSNJAK V, PETKOVIC D, ABDEL-SALAM GM, ABDEL-ALEEM A, ZAKI MS, MARTI I, QUIJANO-ROY S, SIGAUDY S, DE LONLAY P, ROMANO S, VERLOES A, TOURAINE R, KOENIG M, LAGIER-TOURENNE C, MESSER J, COLLIGNON P, WOLF N, PHILIPPI H, LEMKE J, DACOU-VOUTETAKIS C, KITSIOU TZELI S, PONS R, SZTRIHA L, HALLDORSSON S, JOHANNSDOTTIR J, LUDVIGSSON P, PHADKE SR, UDANI V, STUART B, MAGEE A, LEV D, MICHELSON M, BEN-ZEEV B, DI GIACOMO M, GENTILE M, GUANTI G, D'ADDATO O, PAPADIA F, SPANO M, BERNARDI F, SERI M, BENEDICENTI F, STANZIAL F, BORGATTI R, ACCORSI P, BATTAGLIA S, FAZZI E, GIORDANO L, IZZI C, PINELLI L, BOCCONE L, GUANCIALI P, ROMOLI R, BIGONI S, FERLINI A, ANDREUCCI E, DONATI MA, GENUARDI M, CARIDI G, DIVIZIA MT, FARAVELLI F, GHIGGERI G, PESSAGNO, AMORINI M, BRIGUGLIO M, BRIUGLIA S, RIGOLI L, SALPIETRO C, TORTORELLA G, ADAMI A, MARRA G, RIVA D, SCELSA B, SPACCINI L, UZIEL G, COPPOLA G, DEL GIUDICE E, VITIELLO G, LAVERDA AM, LUDWIG K, PERMUNIAN A, SUPPIEJ A, MACALUSO C, SIGNORINI S, UGGETTI C, BATTINI R, PRIOLO M, CILIO MR, D'AMICO A, DI SABATO ML, EMMA F, LEUZZI V, PARISI P, STRINGINI G, ZANNI G, POLLAZZON M, RENIERI A, VASCOTTO M, SILENGO M, DE VESCOVI R, GRECO D, ROMANO C, CAZZAGON M, SIMONATI A, AL-TAWARI AA, BASTAKI L, MÉGARBANÉ A, MATULEVICIENE A, SABOLIC AVRAMOVSKA V, SAID E, DE JONG MM, PRESCOTT T, STROMME P, VON DER LIPPE C, KOUL R, RAJAB A, AZAM M, BARBOT C, JOCIC-JAKUBI B, GENER QUEROL B, MARTORELL SAMPOL L, RODRIGUEZ B, PASCUAL-CASTROVIEJO I, STROZZI S, FLUSS J, TEBER S, TOPCU M, ANLAR B, COMU S, KARACA E, KAYSERILI H, YÜKSEL A, AKGUL M, AKCAKUS M, AL GAZALI L, NICHOLL D, WOODS CG, BENNETT C, HURST J, SHERIDAN E, BARNICOAT A, CARR L, HENNEKAM R, LEES M, MCKAY F, YATES L, BLAIR E, BERNES S, SANCHEZ H, CLARK AE, DEMARCO E, DONAHUE C, SHERR E, HAHN J, SANGER TD, GALLAGER TE, DOBYNS WB, DAUGHERTY C, KRISHNAMOORTHY KS, SARCO D, WALSH CA, MCKANNA T, MILISA J, CJUNG WK, DE VIVO DC, RAYNES H, SCHUBERT R, SEWARD A, BROOKS DG, GOLDSTEIN A, CALDWELL J, FINSECKE E, MARIA BL, HOLDEN K, CRUSE RP, SWOBODA KJ, VISKOCHIL D., Pediatric surgery, NCA - Childhood White Matter Diseases, Iannicelli, M, Brancati, F, Mougou Zerelli, S, Mazzotta, A, Thomas, S, Elkhartoufi, N, Travaglini, L, Gomes, C, Ardissino, Gl, Bertini, E, Boltshauser, E, Castorina, P, D'Arrigo, S, Fischetto, R, Leroy, B, Loget, P, Bonnière, M, Starck, L, Tantau, J, Gentilin, B, Majore, S, Swistun, D, Flori, E, Lalatta, F, Pantaleoni, C, Penzien, J, Grammatico, P, Dallapiccola, B, Gleeson, Jg, Attie Bitach, T, Valente, Em, International JSRD Study, Group, DEL GIUDICE, Ennio, University of Zurich, and Attie-Bitach, T
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Liver Cirrhosis ,2716 Genetics (clinical) ,meckelin ,Ciliopathies ,Joubert syndrome ,Genotype ,congenital hepatic fibrosis ,coach syndrome ,mks3 ,meckel syndrome ,joubert syndrome ,tmem67 ,TMEM67 ,Meckel syndrome ,DNA Mutational Analysis ,610 Medicine & health ,Biology ,medicine.disease_cause ,MKS3 ,COACH syndrome ,Article ,NO ,1311 Genetics ,Nephronophthisis ,Pregnancy ,Prenatal Diagnosis ,Genetics ,medicine ,COACH syndrome, Congenital hepatic fibrosis, Joubert syndrome, Meckel syndrome, MKS3, TMEM67 ,Missense mutation ,Humans ,Abnormalities, Multiple ,Genetics (clinical) ,Mutation ,Cilium ,Membrane Proteins ,Kidney Diseases, Cystic ,medicine.disease ,Phenotype ,10036 Medical Clinic ,Female - Abstract
Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.
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- 2010
21. Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders
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Lorena, Travaglini, Francesco, Brancati, Jennifer, Silhavy, Miriam, Iannicelli, Elizabeth, Nickerson, Nadia, Elkhartoufi, Eric, Scott, Emily, Spencer, Stacey, Gabriel, Sophie, Thomas, Bruria, Ben Zeev, Enrico, Bertini, Eugen, Boltshauser, Malika, Chaouch, Maria, Roberta Cilio, Mirjam, M. de Jong, Hulya, Kayserili, Gonul, Ogur, Andrea, Poretti, Sabrina, Signorini, Graziella, Uziel, Maha, S. Zaki, Ali Pacha, L, Zankl, A, Leventer, R, Grattan Smith, P, Janecke, A, Koch, J, Freilinger, M, D'Hooghe, M, Sznajer, Y, Vilain, C, Van Coster, R, Demerleir, L, Dias, K, Moco, C, Moreira, A, Ae Kim, C, Maegawa, G, Dakovic, I, Loncarevic, D, Mejaski Bosnjak, V, Petkovic, D, Abdel Salam GM, Abdel Aleem, A, Marti, I, Pinard, Jm, Quijano Roy, S, Sigaudy, S, de Lonlay, P, Romano, S, Verloes, A, Touraine, R, Koenig, M, Dollfus, H, Flori, E, Fradin, M, Lagier Tourenne, C, Messer, J, Collignon, P, Penzien, Jm, Bussmann, C, Merkenschlager, A, Philippi, H, Kurlemann, G, Grundmann, K, Dacou Voutetakis, C, Kitsiou Tzeli, S, Pons, R, Jerney, J, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Phadke, Sr, Girisha, Km, Doshi, H, Udani, V, Kaul, M, Stuart, B, Magee, A, Spiegel, R, Shalev, S, Mandel, H, Lev, D, Michelson, M, Idit, M, Ben Zeev, B, Gershoni Baruch, R, Ficcadenti, A, Fischetto, R, Gentile, M, Della Monica, M, Pezzani, M, Graziano, C, Seri, M, Benedicenti, F, Stanzial, F, Borgatti, R, Romaniello, R, Accorsi, P, Battaglia, S, Fazzi, E, Giordano, L, Pinelli, L, Boccone, L, Barone, R, Sorge, G, Briatore, E, Bigoni, S, Ferlini, A, Donati, Ma, Biancheri, R, Caridi, G, Divizia, Mt, Faravelli, F, Ghiggeri, G, Mirabelli, M, Pessagno, A, Rossi, A, Uliana, V, Amorini, M, Briguglio, M, Briuglia, S, Salpietro, Cd, Tortorella, G, Adami, A, Bonati, Mt, Castorina, P, D'Arrigo, S, Lalatta, F, Marra, G, Moroni, I, Pantaleoni, C, Riva, D, Scelsa, B, Spaccini, L, Del Giudice, E, Ludwig, K, Permunian, A, Suppiej, A, Macaluso, C, Pichiecchio, A, Battini, R, Di Giacomo, M, Priolo, M, Timpani, P, Pagani, G, Di Sabato ML, Emma, F, Leuzzi, V, Mancini, F, Majore, S, Micalizzi, A, Parisi, P, Romani, M, Stringini, G, Zanni, G, Ulgheri, L, Pollazzon, M, Renieri, Alessandra, Belligni, E, Grosso, E, Pieri, I, Silengo, M, Devescovi, R, Greco, D, Romano, C, Cazzagon, M, Simonati, A, Al Tawari AA, Bastaki, L, Mégarbané, A, Sabolic Avramovska, V, Said, E, Stromme, P, Koul, R, Rajab, A, Azam, M, Barbot, C, Salih, Ma, Tabarki, B, Jocic Jakubi, B, Martorell Sampol, L, Rodriguez, B, Pascual Castroviejo, I, Gener, B, Puschmann, A, Starck, L, Capone, A, Lemke, J, Fluss, J, Niedrist, D, Hennekam, Rc, Wolf, N, Gouider Khouja, N, Kraoua, I, Ceylaner, S, Teber, S, Akgul, M, Anlar, B, Comu, S, Kayserili, H, Yüksel, A, Akcakus, M, Caglayan, Ao, Aldemir, O, Al Gazali, L, Sztriha, L, Nicholl, D, Woods, Cg, Bennett, C, Hurst, J, Sheridan, E, Barnicoat, A, Hemingway, C, Lees, M, Wakeling, E, Blair, E, Bernes, S, Sanchez, H, Clark, Ae, Demarco, E, Donahue, C, Sherr, E, Hahn, J, Sanger, Td, Gallager, Te, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Walsh, Ca, Mckanna, T, Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Holden, K, Cruse, Rp, Karaca, E, Swoboda, Kj, Viskochil, D, Dobyns, Wb, Colin, Johnson, Tania, Attié Bitach, Joseph, G. Gleeson, Enza, Maria Valente, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Human Genetics, Paediatrics, OMÜ, University of Zurich, Valente, Enza Maria, Fluss, Joel Victor, Travaglini, L, Brancati, F, Silhavy, J, Iannicelli, M, Nickerson, E, Elkhartoufi, N, Scott, E, Spencer, E, Gabriel, S, Thomas, S, Ben Zeev, B, Bertini, E, Boltshauser, E, Chaouch, M, Cilio, Mr, de Jong, Mm, Kayserili, H, Ogur, G, Poretti, A, Signorini, S, Uziel, G, Zaki, M, Johnson, C, Atti? Bitach, T, Gleeson, Jg, Valente, Em, International JSRD Study, Group, and DEL GIUDICE, Ennio
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Male ,Ciliata -- Anatomy ,Proband ,10039 Institute of Medical Genetics ,Meckel syndrome ,RPGRIP1L ,Syndromes ,INPP5E ,MODIFIER ,Phosphoric Monoester Hydrolases/genetics ,Ciliopathies ,Polycystic Kidney Diseases/diagnosis/genetics ,CILIUM ,0302 clinical medicine ,Gene Frequency ,Cerebellum ,Prenatal Diagnosis ,RETINAL DEGENERATION ,Prevalence ,MECKEL ,ciliopathies ,Joubert syndrome and related disorders ,Eye Abnormalities ,Child ,Genetics (clinical) ,Encephalocele ,Joubert syndrome ,Genetics ,Polycystic Kidney Diseases ,0303 health sciences ,ddc:618 ,Cerebellar Diseases/diagnosis/genetics ,Kidney Diseases, Cystic ,Pedigree ,3. Good health ,Phenotype ,Child, Preschool ,Medical genetics ,Female ,Retinitis Pigmentosa ,FORM ,Ciliary Motility Disorders ,Heterozygote ,medicine.medical_specialty ,2716 Genetics (clinical) ,Adolescent ,Molecular Sequence Data ,Encephalocele/diagnosis/genetics ,AHI1 ,610 Medicine & health ,Biology ,Retina ,Article ,Ciliopathies, INPP5E, Joubert syndrome and related disorders, Meckel syndrome ,NO ,Ciliary Motility Disorders/diagnosis/genetics ,03 medical and health sciences ,1311 Genetics ,Cerebellar Diseases ,REVEALS ,medicine ,Humans ,Abnormalities, Multiple ,Amino Acid Sequence ,Kidney Diseases, Cystic/diagnosis/genetics ,abnormalities ,multiple ,adolescent ,amino acid sequence ,cerebellar diseases ,cerebellum ,child ,preschool ,ciliary motility disorders ,encephalocele ,eye abnormalities ,female ,heterozygote ,humans ,infant ,kidney diseases, cystic ,male ,molecular sequence data ,pedigree ,phosphoric monoester hydrolases ,polycystic kidney diseases ,prenatal diagnosis ,prevalence ,retina ,gene frequency ,mutation ,phenotype ,030304 developmental biology ,Eye Abnormalities/diagnosis/genetics ,COACH SYNDROME ,Retina/abnormalities ,Genetic heterogeneity ,Respiration disorders -- Therapy ,Infant ,medicine.disease ,Phosphoric Monoester Hydrolases ,INPP5E mutation ,10036 Medical Clinic ,Mutation ,030217 neurology & neurosurgery - Abstract
Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS foetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus., peer-reviewed
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- 2013
22. MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement
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Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D?arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., Mejaski-Bosnjak, V., Pantaleoni, C., Rigoli, L., Salpietro, C. D., Signorini, S., Stringini, G. R., Verloes, A., Zabloka, D., Dallapiccola, B., Gleeson, J. G., Valente, E. M., Zankl, A., Leventer, R., Smith, P. G., Janecke, A., D?hooghe, M., Sznajer, Y., Van Coster, R., Demerleir, L., Dias, K., Moco, C., Moreira, A., Ae Kim, C., Maegawa, G., Petkovic, D., Abdel-Salam, G. M. H., Abdel-Aleem, A., Zaki, M. S., Marti, I., Quijano-Roy, S., Sigaudy, S., De Lonlay, P., Romano, S., Touraine, R., Koenig, M., Lagier-Tourenne, C., Messer, J., Collignon, P., Wolf, N., Philippi, H., Tzeli, S. K., Halldorsson, S., Johannsdottir, J., Ludvigsson, P., Phadke, S. R., Udani, V., Stuart, B., Magee, A., Lev, D., Michelson, M., Ben-Zeev, B., Fischetto, R., Benedicenti, F., Stanzial, F., Borgatti, R., Accorsi, P., Battaglia, S., Giordano, L., Pinelli, L., Boccone, L., Bigoni, S., Ferlini, A., Donati, M. A., Caridi, G., Divizia, M. T., Faravelli, F., Ghiggeri, G., Pessagno, A., Briuglia, S., Tortorella, G., Adami, A., Castorina, P., Lalatta, F., Marra, G., Riva, D., Scelsa, B., Spaccini, L., Uziel, G., Giudice, E. D., Laverda, A. M., Ludwig, K., Permunian, A., Suppiej, A., Uggetti, C., Battini, R., Giacomo, M. D., Cilio, M. R., Di Sabato, M. L., Leuzzi, V., Parisi, P., Pollazzon, M., Silengo, M., De Vescovi, R., Greco, D., Romano, C., Cazzagon, M., Simonati, A., Al-Tawari, A. A., Bastaki, L., M('e)garban('e), A., Sabolic Avramovska, V., De Jong, M. M., Stromme, P., Koul, R., Rajab, A., Azam, M., Barbot, C., Martorell Sampol, L., Rodriguez, B., Pascual-Castroviejo, I., Teber, S., Anlar, B., Comu, S., Karaca, E., Kayserili, H., Y, Brancati, F, Iannicelli, M, Travaglini, L, Mazzotta, A, Bertini, E, Boltshauser, E, D'Arrigo, S, Emma, F, Fazzi, E, Gallizzi, R, Gentile, M, Loncarevic, D, Mejaski Bosnjak, V, Pantaleoni, C, Rigoli, L, Salpietro, Cd, Signorini, S, Stringini, Gr, Verloes, A, Zabloka, D, Dallapiccola, B, Gleeson, Jg, Valente, Em, International, JSRD Study Group, DEL GIUDICE, Ennio, and Pediatric surgery
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Pathology ,medicine.medical_specialty ,TMEM67 ,DNA Mutational Analysis ,Molecular Sequence Data ,education ,Biology ,Article ,Joubert syndrome ,NO ,MKS3 ,COACH ,Multiple Abnormalities ,Nephronophthisis ,Amino Acid Sequence ,Base Sequence ,Humans ,Liver ,Magnetic Resonance Imaging ,Membrane Proteins ,Mutation ,Phenotype ,RNA Splice Sites ,Syndrome ,Genetics ,medicine ,congenital hepatic fibrosis ,Abnormalities, Multiple ,Meckel syndrome ,COACH syndrome ,Joubert syndrome and related disorders ,Genetics (clinical) ,Aplasia ,medicine.disease ,MKS3/TMEM67 mutation ,COACH Syndrome ,Ciliopathy ,RPGRIP1L ,Congenital hepatic fibrosis ,human activities - Abstract
MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert syndrome related disorder with liver involvement. The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.
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- 2009
23. Clinical and neuroradiological spectrum of biallelic variants in NOTCH3.
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Iruzubieta P, Alves CAPF, Al Shamsi AM, ElGhazali G, Zaki MS, Pinelli L, Lopergolo D, Cho BPH, Jolly AA, Al Futaisi A, Al-Amrani F, Galli J, Fazzi E, Vulin K, Barajas-Olmos F, Hengel H, Aljamal BM, Nasr V, Assarzadegan F, Ragno M, Trojano L, Ojeda NM, Çakar A, Bianchi S, Pescini F, Poggesi A, Al Tenalji A, Aziz M, Mohammad R, Chedrawi A, De Stefano N, Zifarelli G, Schöls L, Haack TB, Rebelo A, Zuchner S, Koc F, Griffiths LR, Orozco L, Helmes KG, Babaei M, Bauer P, Chan Jeong W, Karimiani EG, Schmidts M, Gleeson JG, Chung WK, Alkuraya FS, Shalbafan B, Markus HS, Houlden H, and Maroofian R
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- Humans, Female, Male, Adult, Middle Aged, CADASIL genetics, CADASIL diagnostic imaging, CADASIL pathology, Phenotype, Aged, Mutation, Missense, Genetic Predisposition to Disease, Young Adult, Brain diagnostic imaging, Brain pathology, Adolescent, Receptor, Notch3 genetics, Alleles, Genetic Association Studies, Magnetic Resonance Imaging
- Abstract
Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised., Methods: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants., Findings: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches., Interpretation: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD., Funding: The Wellcome Trust, the MRC., Competing Interests: Declaration of interests Wendy Chung is on the board of directors of Prime Medicine. Stephan Zuchner has received consultancy honoraria from Neurogene, AegleaBioTherapeutics, Applied Therapeutics, and is an unpaid officer of the TGP foundation, all unrelated to the present manuscript. Elisa Fazzi has received honoraria from GW Pharma. Nicola De Stefano has received honoraria from Biogen-Idec, Genzyme, Immunic, Merck, Novartis, Roche, Celgene, and Teva for consulting services, speaking, and travel support. He serves on advisory boards for Merck, Novartis, Biogen-Idec, Immunic, Roche, and Genzyme, and he has received research grant support from the Italian MS Society. Lyn R Griffiths has received grants from the Australian National Health and Medical Research Council, Variant Bio, US Department of Defense and US Migraine Research Foundation as well as honoraria from Teva, Springer Nature, and Association of Migraine Disorders and she is Board of Censors, Diagnostic Genomics Human Genetics Assoc Australia and member of the Human Genetics Australasia Advisory Board. Hugh S Markus has received peer reviewed grants from the Medical Research Council, British Heart Foundation, National Institute of Health Research, and the Alzheimer Society, and is editor in chief of the International Journal of Stroke., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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24. Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.
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Banks E, Francis V, Lin SJ, Kharfallah F, Fonov V, Lévesque M, Han C, Kulasekaran G, Tuznik M, Bayati A, Al-Khater R, Alkuraya FS, Argyriou L, Babaei M, Bahlo M, Bakhshoodeh B, Barr E, Bartik L, Bassiony M, Bertrand M, Braun D, Buchert R, Budetta M, Cadieux-Dion M, Calame DG, Cope H, Cushing D, Efthymiou S, Elmaksoud MA, El Said HG, Froukh T, Gill HK, Gleeson JG, Gogoll L, Goh ES, Gowda VK, Haack TB, Hashem MO, Hauser S, Hoffman TL, Hogue JS, Hosokawa A, Houlden H, Huang K, Huynh S, Karimiani EG, Kaulfuß S, Korenke GC, Kritzer A, Lee H, Lupski JR, Marco EJ, McWalter K, Minassian A, Minassian BA, Murphy D, Neira-Fresneda J, Northrup H, Nyaga DM, Oehl-Jaschkowitz B, Osmond M, Person R, Pehlivan D, Petree C, Sadleir LG, Saunders C, Schoels L, Shashi V, Spillmann RC, Srinivasan VM, Torbati PN, Tos T, Zaki MS, Zhou D, Zweier C, Trempe JF, Durcan TM, Gan-Or Z, Avoli M, Alves C, Varshney GK, Maroofian R, Rudko DA, and McPherson PS
- Subjects
- Humans, Animals, Mice, Neurogenesis genetics, Male, Female, Membrane Proteins metabolism, Membrane Proteins genetics, Guanine Nucleotide Exchange Factors metabolism, Guanine Nucleotide Exchange Factors genetics, Disease Models, Animal, Cell Polarity, Neural Stem Cells metabolism, Neural Stem Cells cytology, Cell Division, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells cytology
- Abstract
Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families., (© 2024. The Author(s).)
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- 2024
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25. Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.
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Ziegler A, Carroll J, Bain JM, Sands TT, Fee RJ, Uher D, Kanner CH, Montes J, Glass S, Douville J, Mignon L, Gleeson JG, Crooke ST, and Chung WK
- Abstract
KIF1A-associated neurological disorder (KAND) is a neurodegenerative and often lethal ultrarare disease with a wide phenotypic spectrum associated with largely heterozygous de novo missense variants in KIF1A. Antisense oligonucleotide treatments represent a promising approach for personalized treatments in ultrarare diseases. Here we report the case of one patient with a severe form of KAND characterized by refractory spells of behavioral arrest and carrying a p.Pro305Leu variant in KIF1A, who was treated with intrathecal injections of an allele-specific antisense oligonucleotide specifically designed to degrade the mRNA from the pathogenic allele. The first intrathecal administration was complicated by an epidural cerebrospinal fluid collection, which resolved spontaneously. Otherwise, the antisense oligonucleotide was safe and well tolerated over the 9-month treatment. Most outcome measures, including severity of the spells of behavioral arrest, number of falls and quality of life, improved. There was little change in the 6-min Walk Test distance, but qualitative changes in gait resulting in meaningful reductions in falls and increasing independence were observed. Cognitive performance was stable and did not degenerate over time. Our findings provide preliminary insights on the safety and efficacy of an allele-specific antisense oligonucleotide as a possible treatment for KAND., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2024
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26. Genome Sequencing for Diagnosing Rare Diseases.
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Wojcik MH, Lemire G, Berger E, Zaki MS, Wissmann M, Win W, White SM, Weisburd B, Wieczorek D, Waddell LB, Verboon JM, VanNoy GE, Töpf A, Tan TY, Syrbe S, Strehlow V, Straub V, Stenton SL, Snow H, Singer-Berk M, Silver J, Shril S, Seaby EG, Schneider R, Sankaran VG, Sanchis-Juan A, Russell KA, Reinson K, Ravenscroft G, Radtke M, Popp D, Polster T, Platzer K, Pierce EA, Place EM, Pajusalu S, Pais L, Õunap K, Osei-Owusu I, Opperman H, Okur V, Oja KT, O'Leary M, O'Heir E, Morel CF, Merkenschlager A, Marchant RG, Mangilog BE, Madden JA, MacArthur D, Lovgren A, Lerner-Ellis JP, Lin J, Laing N, Hildebrandt F, Hentschel J, Groopman E, Goodrich J, Gleeson JG, Ghaoui R, Genetti CA, Gburek-Augustat J, Gazda HT, Ganesh VS, Ganapathi M, Gallacher L, Fu JM, Evangelista E, England E, Donkervoort S, DiTroia S, Cooper ST, Chung WK, Christodoulou J, Chao KR, Cato LD, Bujakowska KM, Bryen SJ, Brand H, Bönnemann CG, Beggs AH, Baxter SM, Bartolomaeus T, Agrawal PB, Talkowski M, Austin-Tse C, Abou Jamra R, Rehm HL, and O'Donnell-Luria A
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- Female, Humans, Male, Cohort Studies, Exome, Exome Sequencing, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn ethnology, Genetic Diseases, Inborn genetics, Genetic Testing, Genome, Human, Phenotype, Sequence Analysis, DNA, Child, Adolescent, Young Adult, Adult, Genetic Variation, Rare Diseases diagnosis, Rare Diseases ethnology, Rare Diseases genetics, Whole Genome Sequencing
- Abstract
Background: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined., Methods: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center., Results: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments., Conclusions: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.)., (Copyright © 2024 Massachusetts Medical Society.)
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- 2024
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27. Risk of meningomyelocele mediated by the common 22q11.2 deletion.
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Vong KI, Lee S, Au KS, Crowley TB, Capra V, Martino J, Haller M, Araújo C, Machado HR, George R, Gerding B, James KN, Stanley V, Jiang N, Alu K, Meave N, Nidhiry AS, Jiwani F, Tang I, Nisal A, Jhamb I, Patel A, Patel A, McEvoy-Venneri J, Barrows C, Shen C, Ha YJ, Howarth R, Strain M, Ashley-Koch AE, Azam M, Mumtaz S, Bot GM, Finnell RH, Kibar Z, Marwan AI, Melikishvili G, Meltzer HS, Mutchinick OM, Stevenson DA, Mroczkowski HJ, Ostrander B, Schindewolf E, Moldenhauer J, Zackai EH, Emanuel BS, Garcia-Minaur S, Nowakowska BA, Stevenson RE, Zaki MS, Northrup H, McNamara HK, Aldinger KA, Phelps IG, Deng M, Glass IA, Morrow B, McDonald-McGinn DM, Sanna-Cherchi S, Lamb DJ, and Gleeson JG
- Subjects
- Animals, Female, Humans, Male, Mice, DiGeorge Syndrome genetics, Exome Sequencing, Folic Acid administration & dosage, Folic Acid Deficiency complications, Folic Acid Deficiency genetics, Penetrance, Spinal Dysraphism genetics, Risk, Adaptor Proteins, Signal Transducing genetics, Chromosome Deletion, Chromosomes, Human, Pair 22 genetics, Meningomyelocele epidemiology, Meningomyelocele genetics
- Abstract
Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl , one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.
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- 2024
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28. Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.
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Lemire G, Sanchis-Juan A, Russell K, Baxter S, Chao KR, Singer-Berk M, Groopman E, Wong I, England E, Goodrich J, Pais L, Austin-Tse C, DiTroia S, O'Heir E, Ganesh VS, Wojcik MH, Evangelista E, Snow H, Osei-Owusu I, Fu J, Singh M, Mostovoy Y, Huang S, Garimella K, Kirkham SL, Neil JE, Shao DD, Walsh CA, Argilli E, Le C, Sherr EH, Gleeson JG, Shril S, Schneider R, Hildebrandt F, Sankaran VG, Madden JA, Genetti CA, Beggs AH, Agrawal PB, Bujakowska KM, Place E, Pierce EA, Donkervoort S, Bönnemann CG, Gallacher L, Stark Z, Tan TY, White SM, Töpf A, Straub V, Fleming MD, Pollak MR, Õunap K, Pajusalu S, Donald KA, Bruwer Z, Ravenscroft G, Laing NG, MacArthur DG, Rehm HL, Talkowski ME, Brand H, and O'Donnell-Luria A
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- Humans, Male, Female, Cohort Studies, Genetic Testing methods, DNA Copy Number Variations genetics, Rare Diseases genetics, Rare Diseases diagnosis, Exome genetics, Exome Sequencing
- Abstract
Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs., Competing Interests: Declaration of interests H.L.R. and M.E.T. have received support from Illumina and Microsoft to support rare disease gene discovery and diagnosis. A.O’D.-L. is on the scientific advisory board for Congenica Inc. D.G.M. is a paid advisor to GlaxoSmithKline, Insitro, Variant Bio, and Overtone Therapeutics and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Google, Merck, Microsoft, Pfizer, and Sanofi-Genzyme. C.A.W. is a paid advisor to Maze Therapeutics. M.E.T. has also received reagents and/or research support from Levo Therapeutics, Pacific Biosciences, Oxford Nanopore, and Ionis Pharmaceuticals., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)
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- 2024
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29. The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children.
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Elkhateeb N, Issa MY, Elbendary HM, Elnaggar W, Ramadan A, Rafat K, Kamel M, Abdel-Ghafar SF, Amer F, Hassaan HM, Trunzo R, Pereira C, Abdel-Hamid MS, D'Arco F, Bauer P, Bertoli-Avella AM, Girgis M, Gleeson JG, Zaki MS, and Selim L
- Subjects
- Child, Humans, Egypt epidemiology, Retrospective Studies, Seizures genetics, Seizures complications, Phenotype, Epilepsy diagnosis, Epilepsy, Generalized
- Abstract
Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2024
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30. Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain.
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Chung C, Yang X, Hevner RF, Kennedy K, Vong KI, Liu Y, Patel A, Nedunuri R, Barton ST, Noel G, Barrows C, Stanley V, Mittal S, Breuss MW, Schlachetzki JCM, Kingsmore SF, and Gleeson JG
- Subjects
- Aged, Female, Humans, Alleles, GABAergic Neurons cytology, GABAergic Neurons metabolism, Hippocampus cytology, Homeodomain Proteins metabolism, Neocortex cytology, Neural Inhibition, Parietal Lobe cytology, Single-Cell Analysis, Transcriptome genetics, Cell Lineage genetics, Clone Cells cytology, Clone Cells metabolism, Mosaicism, Neurons cytology, Neurons metabolism, Prosencephalon anatomy & histology, Prosencephalon cytology, Prosencephalon metabolism
- Abstract
Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain
1-7 . Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior-posterior axis precedes restriction in the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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31. Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.
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Cavusoglu D, Ozturk G, Turkdogan D, Kurul SH, Yis U, Komur M, Incecik F, Kara B, Sahin T, Unver O, Dilber C, Mert GG, Gunay C, Uzan GS, Ersoy O, Oktay Y, Mermer S, Tuncer GO, Gungor O, Ozcora GDK, Gumus U, Sezer O, Cetin GO, Demir F, Yilmaz A, Gurbuz G, Topcu M, Topaloglu H, Ceylan AC, Ceylaner S, Gleeson JG, Icagasioglu DF, and Sonmez FM
- Abstract
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum., (© 2024. The Author(s).)
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- 2024
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32. Neurodevelopmental disorders associated variants in ADAT3 disrupt the activity of the ADAT2/ADAT3 tRNA deaminase complex and impair neuronal migration.
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Del-Pozo-Rodriguez J, Tilly P, Lecat R, Vaca HR, Mosser L, Balla T, Gomes MV, Ramos-Morales E, Brivio E, Salinas-Giégé T, VanNoy G, England EM, Lovgren AK, O'Leary M, Chopra M, Gable D, Alnuzha A, Kamel M, Almenabawy N, O'Donnell-Luria A, Neil JE, Gleeson JG, Walsh CA, Elkhateeb N, Selim L, Srivastava S, Nedialkova DD, Drouard L, Romier C, Bayam E, and Godin JD
- Abstract
The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. In addition, we not only reported 7 new NDD patients carrying biallelic variants in ADAT3 but also deeply characterize the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. We demonstrated that all the identified variants alter both the expression and the activity of the complex leading to a significant decrease of I
34 with direct consequence on their steady-state. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.- Published
- 2024
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33. Bi-allelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome.
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Engal E, Oja KT, Maroofian R, Geminder O, Le TL, Marzin P, Guimier A, Mor E, Zvi N, Elefant N, Zaki MS, Gleeson JG, Muru K, Pajusalu S, Wojcik MH, Pachat D, Elmaksoud MA, Chan Jeong W, Lee H, Bauer P, Zifarelli G, Houlden H, Daana M, Elpeleg O, Amiel J, Lyonnet S, Gordon CT, Harel T, Õunap K, Salton M, and Mor-Shaked H
- Subjects
- Humans, Spliceosomes genetics, Syndrome, Loss of Heterozygosity, Phenotype, Neurodevelopmental Disorders genetics, Intellectual Disability genetics, Intellectual Disability complications, Nervous System Malformations genetics
- Abstract
Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WW domain-binding protein 4 (WBP4) is part of the early spliceosomal complex and has not been previously associated with human pathologies in the Online Mendelian Inheritance in Man (OMIM) database. Through GeneMatcher, we identified ten individuals from eight families with a severe neurodevelopmental syndrome featuring variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal, and gastrointestinal abnormalities. Genetic analysis revealed five different homozygous loss-of-function variants in WBP4. Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated a complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including in genes associated with abnormalities of the nervous system, potentially underlying the phenotypes of the probands. We conclude that bi-allelic variants in WBP4 cause a developmental disorder with variable presentations, adding to the growing list of human spliceosomopathies., Competing Interests: Declaration of interests H.M.-S. is an employee of Geneyx Genomics., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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34. Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases.
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Garrison MA, Jang Y, Bae T, Cherskov A, Emery SB, Fasching L, Jones A, Moldovan JB, Molitor C, Pochareddy S, Peters MA, Shin JH, Wang Y, Yang X, Akbarian S, Chess A, Gage FH, Gleeson JG, Kidd JM, McConnell M, Mills RE, Moran JV, Park PJ, Sestan N, Urban AE, Vaccarino FM, Walsh CA, Weinberger DR, Wheelan SJ, and Abyzov A
- Subjects
- Humans, Autism Spectrum Disorder genetics, Brain, Genomics, Mosaicism, Genome, Human, Mental Disorders genetics
- Abstract
Somatic mosaicism is defined as an occurrence of two or more populations of cells having genomic sequences differing at given loci in an individual who is derived from a single zygote. It is a characteristic of multicellular organisms that plays a crucial role in normal development and disease. To study the nature and extent of somatic mosaicism in autism spectrum disorder, bipolar disorder, focal cortical dysplasia, schizophrenia, and Tourette syndrome, a multi-institutional consortium called the Brain Somatic Mosaicism Network (BSMN) was formed through the National Institute of Mental Health (NIMH). In addition to genomic data of affected and neurotypical brains, the BSMN also developed and validated a best practices somatic single nucleotide variant calling workflow through the analysis of reference brain tissue. These resources, which include >400 terabytes of data from 1087 subjects, are now available to the research community via the NIMH Data Archive (NDA) and are described here., (© 2023. The Author(s).)
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- 2023
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35. SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission.
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Fasham J, Huebner AK, Liebmann L, Khalaf-Nazzal R, Maroofian R, Kryeziu N, Wortmann SB, Leslie JS, Ubeyratna N, Mancini GMS, van Slegtenhorst M, Wilke M, Haack TB, Shamseldin HE, Gleeson JG, Almuhaizea M, Dweikat I, Abu-Libdeh B, Daana M, Zaki MS, Wakeling MN, McGavin L, Turnpenny PD, Alkuraya FS, Houlden H, Schlattmann P, Kaila K, Crosby AH, Baple EL, and Hübner CA
- Subjects
- Child, Mice, Humans, Animals, Mutation genetics, Neurotransmitter Agents, gamma-Aminobutyric Acid genetics, Mammals metabolism, Chloride-Bicarbonate Antiporters genetics, Chloride-Bicarbonate Antiporters metabolism, Sodium-Bicarbonate Symporters genetics, Sodium-Bicarbonate Symporters metabolism, Seizures genetics
- Abstract
SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies, which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2023
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36. Post-zygotic brain mosaicism as a result of partial reversion of pre-zygotic aneuploidy.
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Chung C, Yang X, and Gleeson JG
- Subjects
- Humans, Zygote, Brain, Mosaicism, Aneuploidy
- Published
- 2023
- Full Text
- View/download PDF
37. Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome.
- Author
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Beaman MM, Guidugli L, Hammer M, Barrows C, Gregor A, Lee S, Deak KL, McDonald MT, Jensen C, Zaki MS, Masri AT, Hobbs CA, Gleeson JG, and Cohen JL
- Subjects
- Animals, Humans, Mice, Cerebellum abnormalities, Phenotype, Calpain genetics, Cerebellar Vermis, Dandy-Walker Syndrome diagnosis, Dandy-Walker Syndrome genetics, Microcephaly complications
- Abstract
Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease., (© 2023 Wiley Periodicals LLC.)
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- 2023
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38. Cell-type-resolved somatic mosaicism reveals clonal dynamics of the human forebrain.
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Chung C, Yang X, Hevner RF, Kennedy K, Vong KI, Liu Y, Patel A, Nedunuri R, Barton ST, Barrows C, Stanley V, Mittal S, Breuss MW, Schlachetzki JCM, and Gleeson JG
- Abstract
Debate remains around anatomic origins of specific brain cell subtypes and lineage relationships within the human forebrain. Thus, direct observation in the mature human brain is critical for a complete understanding of the structural organization and cellular origins. Here, we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific Mosaic Variant Barcode Analysis. From four hemispheres from two different human neurotypical donors, we identified 287 and 780 mosaic variants (MVs), respectively that were used to deconvolve clonal dynamics. Clonal spread and allelic fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted compared with resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome-transcriptome analysis at both a cell-type-specific and single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1
+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of MVs across 17 locations within one parietal lobe reveals restrictions of clonal spread in the anterior-posterior axis precedes that of the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus cell-type resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain., Competing Interests: Competing interests K.K. is a senior scientist at Bioskryb Genomics Inc. All other authors declare no competing interests.- Published
- 2023
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39. BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.
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Engel C, Valence S, Delplancq G, Maroofian R, Accogli A, Agolini E, Alkuraya FS, Baglioni V, Bagnasco I, Becmeur-Lefebvre M, Bertini E, Borggraefe I, Brischoux-Boucher E, Bruel AL, Brusco A, Bubshait DK, Cabrol C, Cilio MR, Cornet MC, Coubes C, Danhaive O, Delague V, Denommé-Pichon AS, Di Giacomo MC, Doco-Fenzy M, Engels H, Cremer K, Gérard M, Gleeson JG, Heron D, Goffeney J, Guimier A, Harms FL, Houlden H, Iacomino M, Kaiyrzhanov R, Kamien B, Karimiani EG, Kraus D, Kuentz P, Kutsche K, Lederer D, Massingham L, Mignot C, Morris-Rosendahl D, Nagarajan L, Odent S, Ormières C, Partlow JN, Pasquier L, Penney L, Philippe C, Piccolo G, Poulton C, Putoux A, Rio M, Rougeot C, Salpietro V, Scheffer I, Schneider A, Srivastava S, Straussberg R, Striano P, Valente EM, Venot P, Villard L, Vitobello A, Wagner J, Wagner M, Zaki MS, Zara F, Lesca G, Yassaee VR, Miryounesi M, Hashemi-Gorji F, Beiraghi M, Ashrafzadeh F, Galehdari H, Walsh C, Novelli A, Tacke M, Sadykova D, Maidyrov Y, Koneev K, Shashkin C, Capra V, Zamani M, Van Maldergem L, Burglen L, and Piard J
- Subjects
- Humans, Nuclear Proteins genetics, Phenotype, Genotype, Genetic Association Studies, Atrophy, Epilepsy genetics, Neurodegenerative Diseases genetics
- Abstract
BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17)., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)
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- 2023
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40. Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies.
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Accogli A, Zaki MS, Al-Owain M, Otaif MY, Jackson A, Argilli E, Chandler KE, De Goede CGEL, Cora T, Alvi JR, Eslahi A, Asl Mohajeri MS, Ashtiani S, Au PYB, Scocchia A, Alakurtti K, Pagnamenta AT, Toosi MB, Karimiani EG, Mojarrad M, Arab F, Duymuş F, Scantlebury MH, Yeşil G, Rosenfeld JA, Türkyılmaz A, Sağer SG, Sultan T, Ashrafzadeh F, Zahra T, Rahman F, Maqbool S, Abdel-Hamid MS, Issa MY, Efthymiou S, Bauer P, Zifarelli G, Salpietro V, Al-Hassnan Z, Banka S, Sherr EH, Gleeson JG, Striano P, Houlden H, Severino M, and Maroofian R
- Abstract
LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy and nonspecific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK -related disorder. Exome or genome sequencing was carried out in 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor ('ear-of-the-lynx' sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK -related disorder and expand the list of neurological disorders presenting with the 'ear-of-the-lynx' sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction., Competing Interests: The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2023
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41. Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis.
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Wojcik MH, Lemire G, Zaki MS, Wissman M, Win W, White S, Weisburd B, Waddell LB, Verboon JM, VanNoy GE, Töpf A, Tan TY, Straub V, Stenton SL, Snow H, Singer-Berk M, Silver J, Shril S, Seaby EG, Schneider R, Sankaran VG, Sanchis-Juan A, Russell KA, Reinson K, Ravenscroft G, Pierce EA, Place EM, Pajusalu S, Pais L, Õunap K, Osei-Owusu I, Okur V, Oja KT, O'Leary M, O'Heir E, Morel C, Marchant RG, Mangilog BE, Madden JA, MacArthur D, Lovgren A, Lerner-Ellis JP, Lin J, Laing N, Hildebrandt F, Groopman E, Goodrich J, Gleeson JG, Ghaoui R, Genetti CA, Gazda HT, Ganesh VS, Ganapathy M, Gallacher L, Fu J, Evangelista E, England E, Donkervoort S, DiTroia S, Cooper ST, Chung WK, Christodoulou J, Chao KR, Cato LD, Bujakowska KM, Bryen SJ, Brand H, Bonnemann C, Beggs AH, Baxter SM, Agrawal PB, Talkowski M, Austin-Tse C, Rehm HL, and O'Donnell-Luria A
- Abstract
Background: Causal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort., Methods: GS was performed for 744 individuals with rare disease who were genetically undiagnosed. Analysis included review of single nucleotide, indel, structural, and mitochondrial variants., Results: We successfully solved 218/744 (29.3%) cases using GS, with most solves involving established disease genes (157/218, 72.0%). Of all solved cases, 148 (67.9%) had previously had non-diagnostic ES. We systematically evaluated the 218 causal variants for features requiring GS to identify and 61/218 (28.0%) met these criteria, representing 8.2% of the entire cohort. These included small structural variants (13), copy neutral inversions and complex rearrangements (8), tandem repeat expansions (6), deep intronic variants (15), and coding variants that may be more easily found using GS related to uniformity of coverage (19)., Conclusion: We describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative.
- Published
- 2023
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42. Clinical and molecular spectrum of a large Egyptian cohort with ALS2-related disorders of infantile-onset of clinical continuum IAHSP/JPLS.
- Author
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Zaki MS, Sharaf-Eldin WE, Rafat K, Elbendary HM, Kamel M, Elkhateeb N, Noureldeen MM, Abdeltawab MA, Sadek AA, Essawi ML, Lau T, Murphy D, Abdel-Hamid MS, Holuden H, Issa MY, and Gleeson JG
- Subjects
- Humans, Egypt epidemiology, DNA Mutational Analysis, Mutation, Guanine Nucleotide Exchange Factors genetics
- Abstract
This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter- and intrafamilial variability. We identified 16 homozygous disease-causing ALS2 variants; sorted as splice-site, missense, frameshift, nonsense and in-frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype-genotype correlation., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
43. AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model.
- Author
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Deng R, Medico-Salsench E, Nikoncuk A, Ramakrishnan R, Lanko K, Kühn NA, van der Linde HC, Lor-Zade S, Albuainain F, Shi Y, Yousefi S, Capo I, van den Herik EM, van Slegtenhorst M, van Minkelen R, Geeven G, Mulder MT, Ruijter GJG, Lütjohann D, Jacobs EH, Houlden H, Pagnamenta AT, Metcalfe K, Jackson A, Banka S, De Simone L, Schwaede A, Kuntz N, Palculict TB, Abbas S, Umair M, AlMuhaizea M, Colak D, AlQudairy H, Alsagob M, Pereira C, Trunzo R, Karageorgou V, Bertoli-Avella AM, Bauer P, Bouman A, Hoefsloot LH, van Ham TJ, Issa M, Zaki MS, Gleeson JG, Willemsen R, Kaya N, Arold ST, Maroofian R, Sanderson LE, and Barakat TS
- Subjects
- Animals, Humans, Zebrafish, Mutation, Motor Neurons, Receptors, Autocrine Motility Factor genetics, Spastic Paraplegia, Hereditary drug therapy, Spastic Paraplegia, Hereditary genetics, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
- Abstract
Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction. Whole genome sequencing identified bi-allelic truncating variants in AMFR, encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncating AMFR variants, resulting in a cohort of 20 individuals from 8 unrelated, consanguineous families. Variants segregated with a phenotype of mainly pure but also complex HSP consisting of global developmental delay, mild intellectual disability, motor dysfunction, and progressive spasticity. Patient-derived fibroblasts, neural stem cells (NSCs), and in vivo zebrafish modeling were used to investigate pathomechanisms, including initial preclinical therapy assessment. The absence of AMFR disturbs lipid homeostasis, causing lipid droplet accumulation in NSCs and patient-derived fibroblasts which is rescued upon AMFR re-expression. Electron microscopy indicates ER morphology alterations in the absence of AMFR. Similar findings are seen in amfra-/- zebrafish larvae, in addition to altered touch-evoked escape response and defects in motor neuron branching, phenocopying the HSP observed in patients. Interestingly, administration of FDA-approved statins improves touch-evoked escape response and motor neuron branching defects in amfra-/- zebrafish larvae, suggesting potential therapeutic implications. Our genetic and functional studies identify bi-allelic truncating variants in AMFR as a cause of a novel autosomal recessive HSP by altering lipid metabolism, which may potentially be therapeutically modulated using precision medicine with statins., (© 2023. The Author(s).)
- Published
- 2023
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44. Biallelic loss of function variants in WBP4 , encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome.
- Author
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Engal E, Oja KT, Maroofian R, Geminder O, Le TL, Mor E, Tzvi N, Elefant N, Zaki MS, Gleeson JG, Muru K, Pajusalu S, Wojcik MH, Pachat D, Elmaksoud MA, Jeong WC, Lee H, Bauer P, Zifarelli G, Houlden H, Elpeleg O, Gordon C, Harel T, Õunap K, Salton M, and Mor-Shaked H
- Abstract
Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WBP4 (WW Domain Binding Protein 4) is part of the early spliceosomal complex, and was not described before in the context of human pathologies. Ascertained through GeneMatcher we identified eleven patients from eight families, with a severe neurodevelopmental syndrome with variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal and gastrointestinal abnormalities. Genetic analysis revealed overall five different homozygous loss-of-function variants in WBP4 . Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including enrichment for abnormalities of the nervous system and musculoskeletal system genes, suggesting that the overlapping differentially spliced genes are related to the common phenotypes of the probands. We conclude that biallelic variants in WBP4 cause a spliceosomopathy. Further functional studies are called for better understanding of the mechanism of pathogenicity., Competing Interests: DECLARATION OF INTERESTS HMS is an employee of Geneyx Genomics. Other authors declare no conflict of interest.
- Published
- 2023
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45. Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy.
- Author
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Foronda H, Fu Y, Covarrubias-Pinto A, Bocker HT, González A, Seemann E, Franzka P, Bock A, Bhaskara RM, Liebmann L, Hoffmann ME, Katona I, Koch N, Weis J, Kurth I, Gleeson JG, Reggiori F, Hummer G, Kessels MM, Qualmann B, Mari M, Dikić I, and Hübner CA
- Subjects
- Animals, Humans, Mice, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins deficiency, Membrane Proteins genetics, Membrane Proteins metabolism, Sensory Receptor Cells metabolism, Sensory Receptor Cells pathology, Intracellular Membranes metabolism, Autophagy genetics, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum Stress, Ubiquitinated Proteins metabolism, Ubiquitination
- Abstract
Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy)
1 . Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons2 . Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss3 , interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1-deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance., (© 2023. The Author(s).)- Published
- 2023
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46. Personalized antisense oligonucleotides 'for free, for life' - the n-Lorem Foundation.
- Author
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Gleeson JG, Bennett CF, Carroll JB, Cole T, Douville J, Glass S, Tekendo-Ngongang C, Williford AC, and Crooke ST
- Subjects
- Oligonucleotides, Antisense therapeutic use
- Published
- 2023
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47. Control-independent mosaic single nucleotide variant detection with DeepMosaic.
- Author
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Yang X, Xu X, Breuss MW, Antaki D, Ball LL, Chung C, Shen J, Li C, George RD, Wang Y, Bae T, Cheng Y, Abyzov A, Wei L, Alexandrov LB, Sebat JL, and Gleeson JG
- Subjects
- Whole Genome Sequencing methods, Exome Sequencing, High-Throughput Nucleotide Sequencing methods, Polymorphism, Single Nucleotide genetics, Nucleotides, Software, Exome
- Abstract
Mosaic variants (MVs) reflect mutagenic processes during embryonic development and environmental exposure, accumulate with aging and underlie diseases such as cancer and autism. The detection of noncancer MVs has been computationally challenging due to the sparse representation of nonclonally expanded MVs. Here we present DeepMosaic, combining an image-based visualization module for single nucleotide MVs and a convolutional neural network-based classification module for control-independent MV detection. DeepMosaic was trained on 180,000 simulated or experimentally assessed MVs, and was benchmarked on 619,740 simulated MVs and 530 independent biologically tested MVs from 16 genomes and 181 exomes. DeepMosaic achieved higher accuracy compared with existing methods on biological data, with a sensitivity of 0.78, specificity of 0.83 and positive predictive value of 0.96 on noncancer whole-genome sequencing data, as well as doubling the validation rate over previous best-practice methods on noncancer whole-exome sequencing data (0.43 versus 0.18). DeepMosaic represents an accurate MV classifier for noncancer samples that can be implemented as an alternative or complement to existing methods., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2023
- Full Text
- View/download PDF
48. Stem Cell-Based Organoid Models of Neurodevelopmental Disorders.
- Author
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Wang L, Owusu-Hammond C, Sievert D, and Gleeson JG
- Subjects
- Animals, Humans, Brain, Organoids metabolism, Induced Pluripotent Stem Cells, Neurodevelopmental Disorders genetics, Autistic Disorder metabolism
- Abstract
The past decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders, including Mendelian, de novo, and somatic factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions to support novel therapies. Stem cell-based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror disease-relevant aspects of cellular complexity and developmental timing. These models have brought key insights into neurodevelopmental disorders as diverse as microcephaly, autism, and focal epilepsy. However, intrinsic organoid-to-organoid variability, low levels of certain brain-resident cell types, and long culture times required to reach maturity can impede progress. Several recent advances incorporate specific morphogen gradients, mixtures of diverse brain cell types, and organoid engraftment into animal models. Together with nonhuman primate organoid comparisons, mechanisms of human neurodevelopmental disorders are emerging., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
49. Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing.
- Author
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Owen MJ, Wright MS, Batalov S, Kwon Y, Ding Y, Chau KK, Chowdhury S, Sweeney NM, Kiernan E, Richardson A, Batton E, Baer RJ, Bandoli G, Gleeson JG, Bainbridge M, Chambers CD, and Kingsmore SF
- Subjects
- Child, Female, Humans, Infant, Infant, Newborn, Causality, Cohort Studies, Infant Death, Male, California epidemiology, Infant Mortality, Whole Genome Sequencing
- Abstract
Importance: Understanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood., Objective: To determine the association of genetic diseases with infant mortality., Design, Setting, and Participants: This cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022., Exposure: Infants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation., Main Outcomes and Measures: Proportion of infant deaths associated with single-locus genetic diseases., Results: Among 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission., Conclusions and Relevance: In this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality.
- Published
- 2023
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50. Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.
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Chung C, Yang X, Bae T, Vong KI, Mittal S, Donkels C, Westley Phillips H, Li Z, Marsh APL, Breuss MW, Ball LL, Garcia CAB, George RD, Gu J, Xu M, Barrows C, James KN, Stanley V, Nidhiry AS, Khoury S, Howe G, Riley E, Xu X, Copeland B, Wang Y, Kim SH, Kang HC, Schulze-Bonhage A, Haas CA, Urbach H, Prinz M, Limbrick DD Jr, Gurnett CA, Smyth MD, Sattar S, Nespeca M, Gonda DD, Imai K, Takahashi Y, Chen HH, Tsai JW, Conti V, Guerrini R, Devinsky O, Silva WA Jr, Machado HR, Mathern GW, Abyzov A, Baldassari S, Baulac S, and Gleeson JG
- Subjects
- Humans, Multiomics, Brain metabolism, Mutation, Epilepsy genetics, Malformations of Cortical Development genetics, Malformations of Cortical Development metabolism
- Abstract
Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2023
- Full Text
- View/download PDF
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