1,131 results on '"Gleeson, Joseph G."'
Search Results
2. Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study
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Cavusoglu, Dilek, Ozturk, Gulten, Turkdogan, Dilsad, Kurul, Semra Hiz, Yis, Uluc, Komur, Mustafa, Incecik, Faruk, Kara, Bulent, Sahin, Turkan, Unver, Olcay, Dilber, Cengiz, Mert, Gulen Gul, Gunay, Cagatay, Uzan, Gamze Sarikaya, Ersoy, Ozlem, Oktay, Yavuz, Mermer, Serdar, Tuncer, Gokcen Oz, Gungor, Olcay, Ozcora, Gul Demet Kaya, Gumus, Ugur, Sezer, Ozlem, Cetin, Gokhan Ozan, Demir, Fatma, Yilmaz, Arzu, Gurbuz, Gurkan, Topcu, Meral, Topaloglu, Haluk, Ceylan, Ahmet Cevdet, Ceylaner, Serdar, Gleeson, Joseph G., Icagasioglu, Dilara Fusun, and Sonmez, F. Mujgan
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- 2024
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3. Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies
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Accogli, Andrea, Zaki, Maha S, Al-Owain, Mohammed, Otaif, Mansour Y, Jackson, Adam, Argilli, Emanuela, Chandler, Kate E, De Goede, Christian GEL, Cora, Tülün, Alvi, Javeria Raza, Eslahi, Atieh, Asl Mohajeri, Mahsa Sadat, Ashtiani, Setareh, Au, PY Billie, Scocchia, Alicia, Alakurtti, Kirsi, Pagnamenta, Alistair T, Toosi, Mehran Beiraghi, Ghayoor Karimiani, Ehsan, Mojarrad, Majid, Arab, Fatemeh, Duymuş, Fahrettin, Scantlebury, Morris H, Yeşil, Gözde, Rosenfeld, Jill Anne, Türkyılmaz, Ayberk, Sağer, Safiye Güneş, Sultan, Tipu, Ashrafzadeh, Farah, Zahra, Tatheer, Rahman, Fatima, Maqbool, Shazia, Abdel-Hamid, Mohamed S, Issa, Mahmoud, Efthymiou, Stephanie, Bauer, Peter, Zifarelli, Giovanni, Salpietro, Vincenzo, Al-Hassnan, Zuhair, Banka, Siddharth, Sherr, Elliot H, Gleeson, Joseph G, Striano, Pasquale, Houlden, Henry, Severino, Mariasavina, and Maroofian, Reza
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Pediatric ,Neurosciences ,Genetics ,Neurodegenerative ,Clinical Research ,Congenital Structural Anomalies ,Brain Disorders ,Rare Diseases ,Human Genome ,Epilepsy ,2.1 Biological and endogenous factors ,Aetiology ,Mental health ,Neurological ,Clinical sciences ,Biological psychology - Abstract
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 non-specific 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 eleven families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified twelve distinct homozygous loss-of-function variants in sixteen 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.
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- 2023
4. Clinical and molecular spectrum of a large Egyptian cohort with ALS2‐related disorders of infantile‐onset of clinical continuum IAHSP/JPLS
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Zaki, Maha S, Sharaf‐Eldin, Wessam E, Rafat, Karima, Elbendary, Hasnaa M, Kamel, Mona, Elkhateeb, Nour, Noureldeen, Mahmoud M, Abdeltawab, Mohamed A, Sadek, Abdelrahim A, Essawi, Mona L, Lau, Tracy, Murphy, David, Abdel‐Hamid, Mohamed S, Holuden, Henry, Issa, Mahmoud Y, and Gleeson, Joseph G
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Neurodegenerative ,Clinical Research ,Neurosciences ,Brain Disorders ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Humans ,Egypt ,Guanine Nucleotide Exchange Factors ,DNA Mutational Analysis ,Mutation ,ALS2 ,IAHSP ,JPLS ,UMNL ,Clinical Sciences ,Genetics & Heredity ,Clinical sciences - 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.
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- 2023
5. Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy
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Banks, Emily, Francis, Vincent, Lin, Sheng-Jia, Kharfallah, Fares, Fonov, Vladimir, Lévesque, Maxime, Han, Chanshuai, Kulasekaran, Gopinath, Tuznik, Marius, Bayati, Armin, Al-Khater, Reem, Alkuraya, Fowzan S., Argyriou, Loukas, Babaei, Meisam, Bahlo, Melanie, Bakhshoodeh, Behnoosh, Barr, Eileen, Bartik, Lauren, Bassiony, Mahmoud, Bertrand, Miriam, Braun, Dominique, Buchert, Rebecca, Budetta, Mauro, Cadieux-Dion, Maxime, Calame, Daniel G., Cope, Heidi, Cushing, Donna, Efthymiou, Stephanie, Elmaksoud, Marwa Abd, El Said, Huda G., Froukh, Tawfiq, Gill, Harinder K., Gleeson, Joseph G., Gogoll, Laura, Goh, Elaine S.-Y., Gowda, Vykuntaraju K., Haack, Tobias B., Hashem, Mais O., Hauser, Stefan, Hoffman, Trevor L., Hogue, Jacob S., Hosokawa, Akimoto, Houlden, Henry, Huang, Kevin, Huynh, Stephanie, Karimiani, Ehsan G., Kaulfuß, Silke, Korenke, G. Christoph, Kritzer, Amy, Lee, Hane, Lupski, James R., Marco, Elysa J., McWalter, Kirsty, Minassian, Arakel, Minassian, Berge A., Murphy, David, Neira-Fresneda, Juanita, Northrup, Hope, Nyaga, Denis M., Oehl-Jaschkowitz, Barbara, Osmond, Matthew, Person, Richard, Pehlivan, Davut, Petree, Cassidy, Sadleir, Lynette G., Saunders, Carol, Schoels, Ludger, Shashi, Vandana, Spillmann, Rebecca C., Srinivasan, Varunvenkat M., Torbati, Paria N., Tos, Tulay, Zaki, Maha S., Zhou, Dihong, Zweier, Christiane, Trempe, Jean-François, Durcan, Thomas M., Gan-Or, Ziv, Avoli, Massimo, Alves, Cesar, Varshney, Gaurav K., Maroofian, Reza, Rudko, David A., and McPherson, Peter S.
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- 2024
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6. Control-independent mosaic single nucleotide variant detection with DeepMosaic
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Yang, Xiaoxu, Xu, Xin, Breuss, Martin W, Antaki, Danny, Ball, Laurel L, Chung, Changuk, Shen, Jiawei, Li, Chen, George, Renee D, Wang, Yifan, Bae, Taejeong, Cheng, Yuhe, Abyzov, Alexej, Wei, Liping, Alexandrov, Ludmil B, Sebat, Jonathan L, and Gleeson, Joseph G
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Genetics ,Prevention ,Brain Disorders ,Human Genome ,Underpinning research ,1.1 Normal biological development and functioning ,Software ,Whole Genome Sequencing ,Exome Sequencing ,Exome ,High-Throughput Nucleotide Sequencing ,Polymorphism ,Single Nucleotide ,Nucleotides ,NIMH Brain Somatic Mosaicism Network - 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.
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- 2023
7. Stem Cell–Based Organoid Models of Neurodevelopmental Disorders
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Wang, Lu, Owusu-Hammond, Charlotte, Sievert, David, and Gleeson, Joseph G
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Brain Disorders ,Pediatric ,Stem Cell Research - Nonembryonic - Non-Human ,Biotechnology ,Intellectual and Developmental Disabilities (IDD) ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research ,Regenerative Medicine ,Neurosciences ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Good Health and Well Being ,Animals ,Humans ,Induced Pluripotent Stem Cells ,Brain ,Neurodevelopmental Disorders ,Autistic Disorder ,Organoids ,Assembloid ,Autism ,Brain organoid ,Dominant ,Epilepsy ,Gene-environment-interaction ,Genotype-phenotype ,Microcephaly ,Mosaic ,Mutation ,Neural rosette ,Recessive ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Biological sciences ,Biomedical and clinical sciences ,Psychology - 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.
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- 2023
8. Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing
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Owen, Mallory J, Wright, Meredith S, Batalov, Sergey, Kwon, Yonghyun, Ding, Yan, Chau, Kevin K, Chowdhury, Shimul, Sweeney, Nathaly M, Kiernan, Elizabeth, Richardson, Andrew, Batton, Emily, Baer, Rebecca J, Bandoli, Gretchen, Gleeson, Joseph G, Bainbridge, Matthew, Chambers, Christina D, and Kingsmore, Stephen F
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Epidemiology ,Biomedical and Clinical Sciences ,Health Sciences ,Genetics ,Pediatric ,Infant Mortality ,Clinical Research ,Minority Health ,American Indian or Alaska Native ,Perinatal Period - Conditions Originating in Perinatal Period ,Preterm ,Low Birth Weight and Health of the Newborn ,Health Disparities ,Good Health and Well Being ,Child ,Female ,Humans ,Infant ,Infant ,Newborn ,Causality ,Cohort Studies ,Infant Death ,Male ,Whole Genome Sequencing ,California ,Biomedical and clinical sciences ,Health sciences - Abstract
ImportanceUnderstanding 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.ObjectiveTo determine the association of genetic diseases with infant mortality.Design, setting, and participantsThis 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.ExposureInfants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation.Main outcomes and measuresProportion of infant deaths associated with single-locus genetic diseases.ResultsAmong 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 relevanceIn 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.
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- 2023
9. Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development
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Chung, Changuk, Yang, Xiaoxu, Bae, Taejeong, Vong, Keng Ioi, Mittal, Swapnil, Donkels, Catharina, Westley Phillips, H, Li, Zhen, Marsh, Ashley PL, Breuss, Martin W, Ball, Laurel L, Garcia, Camila Araújo Bernardino, George, Renee D, Gu, Jing, Xu, Mingchu, Barrows, Chelsea, James, Kiely N, Stanley, Valentina, Nidhiry, Anna S, Khoury, Sami, Howe, Gabrielle, Riley, Emily, Xu, Xin, Copeland, Brett, Wang, Yifan, Kim, Se Hoon, Kang, Hoon-Chul, Schulze-Bonhage, Andreas, Haas, Carola A, Urbach, Horst, Prinz, Marco, Limbrick, David D, Gurnett, Christina A, Smyth, Matthew D, Sattar, Shifteh, Nespeca, Mark, Gonda, David D, Imai, Katsumi, Takahashi, Yukitoshi, Chen, Hsin-Hung, Tsai, Jin-Wu, Conti, Valerio, Guerrini, Renzo, Devinsky, Orrin, Silva, Wilson A, Machado, Helio R, Mathern, Gary W, Abyzov, Alexej, Baldassari, Sara, Baulac, Stéphanie, and Gleeson, Joseph G
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Genetics ,Pediatric ,Neurodegenerative ,Epilepsy ,Neurosciences ,Human Genome ,Brain Disorders ,Biotechnology ,Clinical Research ,Stem Cell Research ,Congenital Structural Anomalies ,Underpinning research ,1.1 Normal biological development and functioning ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Humans ,Multiomics ,Brain ,Mutation ,Malformations of Cortical Development ,Focal Cortical Dysplasia Neurogenetics Consortium ,Brain Somatic Mosaicism Network ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - 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.
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- 2023
10. TMEM161B modulates radial glial scaffolding in neocortical development
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Wang, Lu, Heffner, Caleb, Vong, Keng loi, Barrows, Chelsea, Ha, Yoo-Jin, Lee, Sangmoon, Lara-Gonzalez, Pablo, Jhamb, Ishani, Van Der Meer, Dennis, Loughnan, Robert, Parker, Nadine, Sievert, David, Mittal, Swapnil, Issa, Mahmoud Y, Andreassen, Ole A, Dale, Anders, Dobyns, William B, Zaki, Maha S, Murray, Stephen A, and Gleeson, Joseph G
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Genetics ,Clinical Research ,Intellectual and Developmental Disabilities (IDD) ,Brain Disorders ,Neurological ,Animals ,Humans ,Mice ,Ependymoglial Cells ,Mice ,Knockout ,Neocortex ,TMEM161B ,gyrification ,CDC42 ,knock-in crispant mice ,patient-derived brain organoids - Abstract
TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.
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- 2023
11. A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex
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Antaki, Danny, Guevara, James, Maihofer, Adam X, Klein, Marieke, Gujral, Madhusudan, Grove, Jakob, Carey, Caitlin E, Hong, Oanh, Arranz, Maria J, Hervas, Amaia, Corsello, Christina, Vaux, Keith K, Muotri, Alysson R, Iakoucheva, Lilia M, Courchesne, Eric, Pierce, Karen, Gleeson, Joseph G, Robinson, Elise B, Nievergelt, Caroline M, and Sebat, Jonathan
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Genetic Testing ,Prevention ,Intellectual and Developmental Disabilities (IDD) ,Brain Disorders ,Mental Health ,Genetics ,Autism ,Neurosciences ,Pediatric ,2.1 Biological and endogenous factors ,Aetiology ,Autism Spectrum Disorder ,Autistic Disorder ,Child ,Family ,Female ,Genetic Predisposition to Disease ,Humans ,Male ,Multifactorial Inheritance ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.
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- 2022
12. BRAT1–related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients
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Engel, Camille, Valence, Stéphanie, Delplancq, Geoffroy, Maroofian, Reza, Accogli, Andrea, Agolini, Emanuele, Alkuraya, Fowzan S., Baglioni, Valentina, Bagnasco, Irene, Becmeur-Lefebvre, Mathilde, Bertini, Enrico, Borggraefe, Ingo, Brischoux-Boucher, Elise, Bruel, Ange-Line, Brusco, Alfredo, Bubshait, Dalal K., Cabrol, Christelle, Cilio, Maria Roberta, Cornet, Marie-Coralie, Coubes, Christine, Danhaive, Olivier, Delague, Valérie, Denommé-Pichon, Anne-Sophie, Di Giacomo, Marilena Carmela, Doco-Fenzy, Martine, Engels, Hartmut, Cremer, Kirsten, Gérard, Marion, Gleeson, Joseph G., Heron, Delphine, Goffeney, Joanna, Guimier, Anne, Harms, Frederike L., Houlden, Henry, Iacomino, Michele, Kaiyrzhanov, Rauan, Kamien, Benjamin, Karimiani, Ehsan Ghayoor, Kraus, Dror, Kuentz, Paul, Kutsche, Kerstin, Lederer, Damien, Massingham, Lauren, Mignot, Cyril, Morris-Rosendahl, Déborah, Nagarajan, Lakshmi, Odent, Sylvie, Ormières, Clothilde, Partlow, Jennifer Neil, Pasquier, Laurent, Penney, Lynette, Philippe, Christophe, Piccolo, Gianluca, Poulton, Cathryn, Putoux, Audrey, Rio, Marlène, Rougeot, Christelle, Salpietro, Vincenzo, Scheffer, Ingrid, Schneider, Amy, Srivastava, Siddharth, Straussberg, Rachel, Striano, Pasquale, Valente, Enza Maria, Venot, Perrine, Villard, Laurent, Vitobello, Antonio, Wagner, Johanna, Wagner, Matias, Zaki, Maha S., Zara, Federizo, Lesca, Gaetan, Yassaee, Vahid Reza, Miryounesi, Mohammad, Hashemi-Gorji, Farzad, Beiraghi, Mehran, Ashrafzadeh, Farah, Galehdari, Hamid, Walsh, Christopher, Novelli, Antonio, Tacke, Moritz, Sadykova, Dinara, Maidyrov, Yerdan, Koneev, Kairgali, Shashkin, Chingiz, Capra, Valeria, Zamani, Mina, Van Maldergem, Lionel, Burglen, Lydie, and Piard, Juliette
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- 2023
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13. Biallelic FRA10AC1 variants cause a neurodevelopmental disorder with growth retardation.
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von Elsner, Leonie, Chai, Guoliang, Schneeberger, Pauline E, Harms, Frederike L, Casar, Christian, Qi, Minyue, Alawi, Malik, Abdel-Salam, Ghada MH, Zaki, Maha S, Arndt, Florian, Yang, Xiaoxu, Stanley, Valentina, Hempel, Maja, Gleeson, Joseph G, and Kutsche, Kerstin
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Brain Disorders ,Neurosciences ,Clinical Research ,Intellectual and Developmental Disabilities (IDD) ,Rare Diseases ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,DNA-Binding Proteins ,Growth Disorders ,Humans ,Intellectual Disability ,Membrane Proteins ,Microcephaly ,Neurodevelopmental Disorders ,Nuclear Proteins ,RNA Splice Sites ,RNA-Binding Proteins ,Repressor Proteins ,exome sequencing ,homozygous ,major spliceosome ,splicing ,intellectual disability ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5' and 3' splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction with splice sites. We identified biallelic pathogenic variants in FRA10AC1 in five individuals from three consanguineous families. The two unrelated Patients 1 and 2 with loss-of-function variants showed developmental delay, intellectual disability, and no speech, while three siblings with the c.494_496delAAG (p.Glu165del) variant had borderline to mild intellectual disability. All patients had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. FRA10AC1 transcripts and proteins were drastically reduced or absent in fibroblasts of Patients 1 and 2. In a heterologous expression system, the p.Glu165del variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localization. By co-immunoprecipitation, we found ectopically expressed HA-FRA10AC1 in complex with endogenous DGCR14, another component of the spliceosomal C complex, while the splice factors CHERP, NKAP, RED, and SF3B2 could not be co-immunoprecipitated. Using an in vitro splicing reporter assay, we did not obtain evidence for FRA10AC1 deficiency to suppress missplicing events caused by mutations in the highly conserved dinucleotides of 5' and 3' splice sites in an in vitro splicing assay in patient-derived fibroblasts. Our data highlight the importance of specific peripheral spliceosomal C complex proteins for neurodevelopment. It remains possible that FRA10AC1 may have other and/or additional cellular functions, such as coupling of transcription and splicing reactions.
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- 2022
14. Somatic mosaicism reveals clonal distributions of neocortical development
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Breuss, Martin W, Yang, Xiaoxu, Schlachetzki, Johannes CM, Antaki, Danny, Lana, Addison J, Xu, Xin, Chung, Changuk, Chai, Guoliang, Stanley, Valentina, Song, Qiong, Newmeyer, Traci F, Nguyen, An, O’Brien, Sydney, Hoeksema, Marten A, Cao, Beibei, Nott, Alexi, McEvoy-Venneri, Jennifer, Pasillas, Martina P, Barton, Scott T, Copeland, Brett R, Nahas, Shareef, Van Der Kraan, Lucitia, Ding, Yan, Glass, Christopher K, and Gleeson, Joseph G
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Neurosciences ,Stem Cell Research - Nonembryonic - Non-Human ,Stem Cell Research ,Neurological ,Cell Lineage ,Cells ,Cultured ,Clone Cells ,Humans ,Microglia ,Mosaicism ,Neocortex ,NIMH Brain Somatic Mosaicism Network ,General Science & Technology - Abstract
The structure of the human neocortex underlies species-specific traits and reflects intricate developmental programs. Here we sought to reconstruct processes that occur during early development by sampling adult human tissues. We analysed neocortical clones in a post-mortem human brain through a comprehensive assessment of brain somatic mosaicism, acting as neutral lineage recorders1,2. We combined the sampling of 25 distinct anatomic locations with deep whole-genome sequencing in a neurotypical deceased individual and confirmed results with 5 samples collected from each of three additional donors. We identified 259 bona fide mosaic variants from the index case, then deconvolved distinct geographical, cell-type and clade organizations across the brain and other organs. We found that clones derived after the accumulation of 90-200 progenitors in the cerebral cortex tended to respect the midline axis, well before the anterior-posterior or ventral-dorsal axes, representing a secondary hierarchy following the overall patterning of forebrain and hindbrain domains. Clones across neocortically derived cells were consistent with a dual origin from both dorsal and ventral cellular populations, similar to rodents, whereas the microglia lineage appeared distinct from other resident brain cells. Our data provide a comprehensive analysis of brain somatic mosaicism across the neocortex and demonstrate cellular origins and progenitor distribution patterns within the human brain.
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- 2022
15. A Zika virus mutation enhances transmission potential and confers escape from protective dengue virus immunity
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Regla-Nava, Jose Angel, Wang, Ying-Ting, Fontes-Garfias, Camila R, Liu, Yang, Syed, Thasneem, Susantono, Mercylia, Gonzalez, Andrew, Viramontes, Karla M, Verma, Shailendra Kumar, Kim, Kenneth, Landeras-Bueno, Sara, Huang, Chun-Teng, Prigozhin, Daniil M, Gleeson, Joseph G, Terskikh, Alexey V, Shi, Pei-Yong, and Shresta, Sujan
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Biological Sciences ,Rare Diseases ,Vaccine Related ,Prevention ,Emerging Infectious Diseases ,Infectious Diseases ,Vector-Borne Diseases ,Biodefense ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Good Health and Well Being ,Animals ,Antibodies ,Viral ,Cross Reactions ,Dengue ,Dengue Virus ,Mice ,Mutation ,Zika Virus ,Zika Virus Infection ,CP: Microbiology ,Flavivirus evolution ,cross-protective immunity ,dengue virus ,mouse-adapted virus ,viral pathogenesis ,viral transmission ,viral variants ,zika virus ,Biochemistry and Cell Biology ,Medical Physiology ,Biological sciences - Abstract
Zika virus (ZIKV) and dengue virus (DENV) are arthropod-borne pathogenic flaviviruses that co-circulate in many countries. To understand some of the pressures that influence ZIKV evolution, we mimic the natural transmission cycle by repeating serial passaging of ZIKV through cultured mosquito cells and either DENV-naive or DENV-immune mice. Compared with wild-type ZIKV, the strains passaged under both conditions exhibit increased pathogenesis in DENV-immune mice. Application of reverse genetics identifies an isoleucine-to-valine mutation (I39V) in the NS2B proteins of both passaged strains that confers enhanced fitness and escape from pre-existing DENV immunity. Introduction of I39V or I39T, a naturally occurring homologous mutation detected in recent ZIKV isolates, increases the replication of wild-type ZIKV in human neuronal precursor cells and laboratory-raised mosquitoes. Our data indicate that ZIKV strains with enhanced transmissibility and pathogenicity can emerge in DENV-naive or -immune settings, and that NS2B-I39 mutants may represent ZIKV variants of interest.
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- 2022
16. Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease
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Lemire, Gabrielle, Sanchis-Juan, Alba, Russell, Kathryn, Baxter, Samantha, Chao, Katherine R., Singer-Berk, Moriel, Groopman, Emily, Wong, Isaac, England, Eleina, Goodrich, Julia, Pais, Lynn, Austin-Tse, Christina, DiTroia, Stephanie, O’Heir, Emily, Ganesh, Vijay S., Wojcik, Monica H., Evangelista, Emily, Snow, Hana, Osei-Owusu, Ikeoluwa, Fu, Jack, Singh, Mugdha, Mostovoy, Yulia, Huang, Steve, Garimella, Kiran, Kirkham, Samantha L., Neil, Jennifer E., Shao, Diane D., Walsh, Christopher A., Argilli, Emanuela, Le, Carolyn, Sherr, Elliott H., Gleeson, Joseph G., Shril, Shirlee, Schneider, Ronen, Hildebrandt, Friedhelm, Sankaran, Vijay G., Madden, Jill A., Genetti, Casie A., Beggs, Alan H., Agrawal, Pankaj B., Bujakowska, Kinga M., Place, Emily, Pierce, Eric A., Donkervoort, Sandra, Bönnemann, Carsten G., Gallacher, Lyndon, Stark, Zornitza, Tan, Tiong Yang, White, Susan M., Töpf, Ana, Straub, Volker, Fleming, Mark D., Pollak, Martin R., Õunap, Katrin, Pajusalu, Sander, Donald, Kirsten A., Bruwer, Zandre, Ravenscroft, Gianina, Laing, Nigel G., MacArthur, Daniel G., Rehm, Heidi L., Talkowski, Michael E., Brand, Harrison, and O’Donnell-Luria, Anne
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- 2024
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17. Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases
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Garrison, McKinzie A., Jang, Yeongjun, Bae, Taejeong, Cherskov, Adriana, Emery, Sarah B., Fasching, Liana, Jones, Attila, Moldovan, John B., Molitor, Cindy, Pochareddy, Sirisha, Peters, Mette A., Shin, Joo Heon, Wang, Yifan, Yang, Xiaoxu, Akbarian, Schahram, Chess, Andrew, Gage, Fred H., Gleeson, Joseph G., Kidd, Jeffrey M., McConnell, Michael, Mills, Ryan E., Moran, John V., Park, Peter J., Sestan, Nenad, Urban, Alexander E., Vaccarino, Flora M., Walsh, Christopher A., Weinberger, Daniel R., Wheelan, Sarah J., and Abyzov, Alexej
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- 2023
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18. Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission
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Breuss, Martin W, Yang, Xiaoxu, Stanley, Valentina, McEvoy-Venneri, Jennifer, Xu, Xin, Morales, Arlene J, and Gleeson, Joseph G
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Clinical Sciences ,Reproductive Medicine ,Pediatric ,Human Genome ,Contraception/Reproduction ,Clinical Research ,Good Health and Well Being ,Child ,Cohort Studies ,Humans ,Male ,Mosaicism ,Semen ,Software ,Spermatozoa ,sperm ,mosaicism ,de novo mutation ,blastocyst ,IVF ,Human ,genetics ,genomics ,human ,medicine ,Biochemistry and Cell Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundDe novo mutations underlie individually rare but collectively common pediatric congenital disorders. Some of these mutations can also be detected in tissues and from cells in a parent, where their abundance and tissue distribution can be measured. We previously reported that a subset of these mutations is detectable in sperm from the father, predicted to impact the health of offspring.MethodsAs a cohort study, in three independent couples undergoing in vitro fertilization, we first identified male gonadal mosaicism through deep whole genome sequencing. We then confirmed variants and assessed their transmission to preimplantation blastocysts (32 total) through targeted ultra-deep genotyping.ResultsAcross 55 gonadal mosaic variants, 15 were transmitted to blastocysts for a total of 19 transmission events. This represented an overall predictable but slight undertransmission based upon the measured mutational abundance in sperm. We replicated this conclusion in an independent, previously published family-based cohort.ConclusionsUnbiased preimplantation genetic testing for gonadal mosaicism may represent a feasible approach to reduce the transmission of potentially harmful de novo mutations. This-in turn-could help to reduce their impact on miscarriages and pediatric disease.FundingNo external funding was received for this work.
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- 2022
19. AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model
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Deng, Ruizhi, Medico-Salsench, Eva, Nikoncuk, Anita, Ramakrishnan, Reshmi, Lanko, Kristina, Kühn, Nikolas A., van der Linde, Herma C., Lor-Zade, Sarah, Albuainain, Fatimah, Shi, Yuwei, Yousefi, Soheil, Capo, Ivan, van den Herik, Evita Medici, van Slegtenhorst, Marjon, van Minkelen, Rick, Geeven, Geert, Mulder, Monique T., Ruijter, George J. G., Lütjohann, Dieter, Jacobs, Edwin H., Houlden, Henry, Pagnamenta, Alistair T., Metcalfe, Kay, Jackson, Adam, Banka, Siddharth, De Simone, Lenika, Schwaede, Abigail, Kuntz, Nancy, Palculict, Timothy Blake, Abbas, Safdar, Umair, Muhammad, AlMuhaizea, Mohammed, Colak, Dilek, AlQudairy, Hanan, Alsagob, Maysoon, Pereira, Catarina, Trunzo, Roberta, Karageorgou, Vasiliki, Bertoli-Avella, Aida M., Bauer, Peter, Bouman, Arjan, Hoefsloot, Lies H., van Ham, Tjakko J., Issa, Mahmoud, Zaki, Maha S., Gleeson, Joseph G., Willemsen, Rob, Kaya, Namik, Arold, Stefan T., Maroofian, Reza, Sanderson, Leslie E., and Barakat, Tahsin Stefan
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- 2023
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20. Comprehensive identification of somatic nucleotide variants in human brain tissue
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Wang, Yifan, Bae, Taejeong, Thorpe, Jeremy, Sherman, Maxwell A, Jones, Attila G, Cho, Sean, Daily, Kenneth, Dou, Yanmei, Ganz, Javier, Galor, Alon, Lobon, Irene, Pattni, Reenal, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Yang, Xiaoxu, Zhou, Bo, Akbarian, Schahram, Ball, Laurel L, Bizzotto, Sara, Emery, Sarah B, Doan, Ryan, Fasching, Liana, Jang, Yeongjun, Juan, David, Lizano, Esther, Luquette, Lovelace J, Moldovan, John B, Narurkar, Rujuta, Oetjens, Matthew T, Rodin, Rachel E, Sekar, Shobana, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E, Zhou, Weichen, Chess, Andrew, Gleeson, Joseph G, Marquès-Bonet, Tomas, Park, Peter J, Peters, Mette A, Pevsner, Jonathan, Walsh, Christopher A, Weinberger, Daniel R, Vaccarino, Flora M, Moran, John V, Urban, Alexander E, Kidd, Jeffrey M, Mills, Ryan E, and Abyzov, Alexej
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Neurosciences ,Human Genome ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Alleles ,Brain ,Chromosome Mapping ,Computational Biology ,Genetic Association Studies ,Genetic Variation ,Genomics ,Germ Cells ,High-Throughput Nucleotide Sequencing ,Humans ,Organ Specificity ,Polymorphism ,Single Nucleotide ,Brain Somatic Mosaicism Network ,Environmental Sciences ,Information and Computing Sciences ,Bioinformatics - Abstract
BackgroundPost-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.ResultsHere, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees.ConclusionsThis study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.
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- 2021
21. Sperm mosaicism: implications for genomic diversity and disease
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Breuss, Martin W, Yang, Xiaoxu, and Gleeson, Joseph G
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Human Genome ,Biotechnology ,Contraception/Reproduction ,Pediatric ,Genetics ,Disease ,Genomics ,Humans ,Male ,Mosaicism ,Mutation ,Spermatogonia ,Spermatozoa ,advanced paternal age ,human variation ,primordial germ cells ,sperm mosaicism ,spermatogonial stem cells ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
While sperm mosaicism has few consequences for men, the offspring and future generations are unwitting recipients of gonadal cell mutations, often yielding severe disease. Recent studies, fueled by emergent technologies, show that sperm mosaicism is a common source of de novo mutations (DNMs) that underlie severe pediatric disease as well as human genetic diversity. Sperm mosaicism can be divided into three types: Type I arises during sperm meiosis and is non-age dependent; Type II arises in spermatogonia and increases as men age; and Type III arises during paternal embryogenesis, spreads throughout the body, and contributes stably to sperm throughout life. Where Types I and II confer little risk of recurrence, Type III may confer identifiable risk to future offspring. These mutations are likely to be the single largest contributor to human genetic diversity. New sequencing approaches may leverage this framework to evaluate and reduce disease risk for future generations.
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- 2021
22. A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion
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Chai, Guoliang, Szenker-Ravi, Emmanuelle, Chung, Changuk, Li, Zhen, Wang, Lu, Khatoo, Muznah, Marshall, Trevor, Jiang, Nan, Yang, Xiaoxu, McEvoy-Venneri, Jennifer, Stanley, Valentina, Anzenberg, Paula, Lang, Nhi, Wazny, Vanessa, Yu, Jia, Virshup, David M, Nygaard, Rie, Mancia, Filippo, Merdzanic, Rijad, Toralles, Maria BP, Pitanga, Paula ML, Puri, Ratna D, Hernan, Rebecca, Chung, Wendy K, Bertoli-Avella, Aida M, Al-Sannaa, Nouriya, Zaki, Maha S, Willert, Karl, Reversade, Bruno, and Gleeson, Joseph G
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Biotechnology ,Rare Diseases ,Genetics ,Human Genome ,Brain Disorders ,Pediatric Research Initiative ,Congenital Structural Anomalies ,Pediatric ,Aetiology ,2.1 Biological and endogenous factors ,Abnormalities ,Multiple ,Animals ,Congenital Abnormalities ,Disease Models ,Animal ,Fibroblasts ,Gene Knock-In Techniques ,Genes ,Recessive ,Genetic Pleiotropy ,Humans ,Intracellular Signaling Peptides and Proteins ,Mice ,Mice ,Transgenic ,Mutation ,Pedigree ,Phenotype ,Receptors ,G-Protein-Coupled ,Syndrome ,Wnt Proteins ,Wnt Signaling Pathway ,Medical and Health Sciences ,General & Internal Medicine - Abstract
BackgroundStructural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach.MethodsWe queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant "knocked in," to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring.ResultsWe identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development.ConclusionsGenetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder. (Funded by the National Institutes of Health and others.).
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- 2021
23. Developmental and temporal characteristics of clonal sperm mosaicism
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Yang, Xiaoxu, Breuss, Martin W, Xu, Xin, Antaki, Danny, James, Kiely N, Stanley, Valentina, Ball, Laurel L, George, Renee D, Wirth, Sara A, Cao, Beibei, Nguyen, An, McEvoy-Venneri, Jennifer, Chai, Guoliang, Nahas, Shareef, Van Der Kraan, Lucitia, Ding, Yan, Sebat, Jonathan, and Gleeson, Joseph G
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Human Genome ,Stem Cell Research ,Aetiology ,Underpinning research ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Generic health relevance ,Adolescent ,Aging ,Alleles ,Clone Cells ,Cohort Studies ,Growth and Development ,Humans ,Male ,Models ,Biological ,Mosaicism ,Mutation ,Risk Factors ,Spermatozoa ,Time Factors ,Young Adult ,autism spectrum disorder ,clonal mosaicism ,congenital disorders ,de novo mutation ,embryogenesis ,mutational signature ,somatic ,sperm ,transmission risk ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.
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- 2021
24. Post-zygotic brain mosaicism as a result of partial reversion of pre-zygotic aneuploidy
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Chung, Changuk, Yang, Xiaoxu, and Gleeson, Joseph G.
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- 2023
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25. A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome
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Ghosh, Shereen G, Scala, Marcello, Beetz, Christian, Helman, Guy, Stanley, Valentina, Yang, Xiaoxu, Breuss, Martin W, Mazaheri, Neda, Selim, Laila, Hadipour, Fatemeh, Pais, Lynn, Stutterd, Chloe A, Karageorgou, Vasiliki, Begtrup, Amber, Crunk, Amy, Juusola, Jane, Willaert, Rebecca, Flore, Leigh A, Kennelly, Kelly, Spencer, Christopher, Brown, Martha, Trapane, Pamela, Hurst, Anna CE, Lane Rutledge, S, Goodloe, Dana H, McDonald, Marie T, Shashi, Vandana, Schoch, Kelly, Tomoum, Hoda, Zaitoun, Raghda, Hadipour, Zahra, Galehdari, Hamid, Pagnamenta, Alistair T, Mojarrad, Majid, Sedaghat, Alireza, Dias, Patrícia, Quintas, Sofia, Eslahi, Atiyeh, Shariati, Gholamreza, Bauer, Peter, Simons, Cas, Houlden, Henry, Issa, Mahmoud Y, Zaki, Maha S, Maroofian, Reza, and Gleeson, Joseph G
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Biological Sciences ,Genetics ,Brain Disorders ,Rare Diseases ,Clinical Research ,Neurosciences ,Human Genome ,Pediatric ,Neurodegenerative ,Intellectual and Developmental Disabilities (IDD) ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Child ,Preschool ,Codon ,Nonsense ,Exome ,Exons ,Female ,Homozygote ,Humans ,Male ,Microcephaly ,Nerve Tissue Proteins ,Neurodevelopmental Disorders ,Pedigree ,RNA Splice Sites ,RNA Splicing ,Syndrome ,Vesicular Transport Proteins ,Undiagnosed Diseases Network ,Clinical Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.
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- 2021
26. Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly
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Chai, Guoliang, Webb, Alice, Li, Chen, Antaki, Danny, Lee, Sangmoon, Breuss, Martin W, Lang, Nhi, Stanley, Valentina, Anzenberg, Paula, Yang, Xiaoxu, Marshall, Trevor, Gaffney, Patrick, Wierenga, Klaas J, Chung, Brian Hon-Yin, Tsang, Mandy Ho-Yin, Pais, Lynn S, Lovgren, Alysia Kern, VanNoy, Grace E, Rehm, Heidi L, Mirzaa, Ghayda, Leon, Eyby, Diaz, Jullianne, Neumann, Alexander, Kalverda, Arnout P, Manfield, Iain W, Parry, David A, Logan, Clare V, Johnson, Colin A, Bonthron, David T, Valleley, Elizabeth MA, Issa, Mahmoud Y, Abdel-Ghafar, Sherif F, Abdel-Hamid, Mohamed S, Jennings, Patricia, Zaki, Maha S, Sheridan, Eamonn, and Gleeson, Joseph G
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Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Rare Diseases ,Genetics ,Neurodegenerative ,Brain Disorders ,Orphan Drug ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Amino Acid Sequence ,Animals ,Cell Cycle Proteins ,Cerebellar Diseases ,Cohort Studies ,Female ,Gene Knockout Techniques ,HEK293 Cells ,Heredodegenerative Disorders ,Nervous System ,Humans ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Microcephaly ,Mutation ,Pedigree ,Peptidylprolyl Isomerase ,Protein Structure ,Secondary ,Protein Structure ,Tertiary ,RNA Splicing Factors ,Spliceosomes ,NMR ,PCHM ,PPIL1 ,PRP17 ,alternative splicing ,brain development ,cyclophilin ,microcephaly ,neurodegeneration ,pontocerebellar hypoplasia ,proline isomerase ,recessive disease ,spliceosome ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.
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- 2021
27. Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families
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Issa, Mahmoud Y, Chechlacz, Zinayida, Stanley, Valentina, George, Renee D, McEvoy-Venneri, Jennifer, Belandres, Denice, Elbendary, Hasnaa M, Gaber, Khaled R, Nabil, Ahmed, Abdel-Hamid, Mohamed S, Zaki, Maha S, and Gleeson, Joseph G
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Reproductive Medicine ,Biomedical and Clinical Sciences ,Genetics ,Biological Sciences ,Prevention ,Pediatric ,Clinical Research ,Reproductive health and childbirth ,Good Health and Well Being ,Child ,Preschool ,Female ,Genes ,Recessive ,Genetic Markers ,Genetic Predisposition to Disease ,Genetic Testing ,Genotype ,High-Throughput Nucleotide Sequencing ,Humans ,Infant ,Infant ,Newborn ,Male ,Mutation ,Nervous System Diseases ,Pedigree ,Pregnancy ,Prenatal Diagnosis ,Recurrence ,Retrospective Studies ,Medical Biochemistry and Metabolomics ,Oncology and Carcinogenesis ,Genetics & Heredity ,Medical biochemistry and metabolomics - Abstract
BackgroundThe causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.MethodsRetrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.ResultsBetween 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011).ConclusionsMolecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.
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- 2020
28. Closing in on Mechanisms of Open Neural Tube Defects
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Lee, Sangmoon and Gleeson, Joseph G
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Research ,Pediatric ,Infant Mortality ,Genetics ,Congenital Structural Anomalies ,Nutrition ,Prevention ,Rare Diseases ,Human Genome ,Spina Bifida ,Neurological ,Good Health and Well Being ,Folic Acid ,Humans ,Neural Tube Defects ,anencephaly ,folate ,folic acid ,myelomeningocele ,neural tube defect ,spina bifida ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology ,Clinical and health psychology - Abstract
Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of the CNS. Following mandatory folic acid fortification of dietary grains, a dramatic reduction in the incidence of NTDs was observed in areas where the policy was implemented, yet the genetic drivers of NTDs in humans, and the mechanisms by which folic acid prevents disease, remain disputed. Here, we discuss current understanding of human NTD genetics, recent advances regarding potential mechanisms by which folic acid might modify risk through effects on the epigenome and transcriptome, and new approaches to study refined phenotypes for a greater appreciation of the developmental and genetic causes of NTDs.
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- 2020
29. Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
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Coulter, Michael E, Musaev, Damir, DeGennaro, Ellen M, Zhang, Xiaochang, Henke, Katrin, James, Kiely N, Smith, Richard S, Hill, R Sean, Partlow, Jennifer N, Muna Al-Saffar, Kamumbu, A Stacy, Hatem, Nicole, Barkovich, A James, Aziza, Jacqueline, Chassaing, Nicolas, Zaki, Maha S, Sultan, Tipu, Burglen, Lydie, Rajab, Anna, Al-Gazali, Lihadh, Mochida, Ganeshwaran H, Harris, Matthew P, Gleeson, Joseph G, and Walsh, Christopher A
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Genetics ,Pediatric ,Brain Disorders ,Congenital Structural Anomalies ,Rare Diseases ,Mental Health ,Neurodegenerative ,Neurosciences ,Clinical Research ,Intellectual and Developmental Disabilities (IDD) ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Aetiology ,Underpinning research ,Neurological ,Animals ,Brain Diseases ,Cell Proliferation ,Homozygote ,Humans ,Mice ,Microcephaly ,Zebrafish ,exocyst ,EXOC7 ,EXOC8 ,microcephaly ,developmental delay ,Clinical Sciences ,Genetics & Heredity - Abstract
PurposeThe exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown.MethodsWe performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout.ResultsWe report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly.ConclusionOur results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.
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- 2020
30. Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism
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Wenderski, Wendy, Wang, Lu, Krokhotin, Andrey, Walsh, Jessica J, Li, Hongjie, Shoji, Hirotaka, Ghosh, Shereen, George, Renee D, Miller, Erik L, Elias, Laura, Gillespie, Mark A, Son, Esther Y, Staahl, Brett T, Baek, Seung Tae, Stanley, Valentina, Moncada, Cynthia, Shipony, Zohar, Linker, Sara B, Marchetto, Maria CN, Gage, Fred H, Chen, Dillon, Sultan, Tipu, Zaki, Maha S, Ranish, Jeffrey A, Miyakawa, Tsuyoshi, Luo, Liqun, Malenka, Robert C, Crabtree, Gerald R, and Gleeson, Joseph G
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Autism ,Behavioral and Social Science ,Basic Behavioral and Social Science ,Pediatric ,Intellectual and Developmental Disabilities (IDD) ,Mental Health ,Neurosciences ,Genetics ,Brain Disorders ,1.1 Normal biological development and functioning ,Aetiology ,2.1 Biological and endogenous factors ,Underpinning research ,Neurological ,Mental health ,Actins ,Adenosine Triphosphate ,Animals ,Autism Spectrum Disorder ,Behavior ,Animal ,Chromatin ,Chromatin Assembly and Disassembly ,Chromosomal Proteins ,Non-Histone ,Chromosome Pairing ,Corpus Callosum ,DNA-Binding Proteins ,Dendrites ,Disease Models ,Animal ,Gene Expression Regulation ,Hippocampus ,Humans ,Mice ,Mice ,Knockout ,Mutation ,Neurons ,Transcription Factors ,autism ,mouse model ,recessive ,BAF ,activity dependent - Abstract
Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit ACTL6B (originally named BAF53b). Accordingly, ACTL6B was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking ACTL6B showed corpus callosum hypoplasia, indicating a conserved role for ACTL6B in facilitating neural connectivity. Actl6b knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors (Fos, Fosl2, Fosb, and Junb), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. ACTL6B loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.
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- 2020
31. Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly
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Ghosh, Shereen Georges, Wang, Lu, Breuss, Martin W, Green, Joshua D, Stanley, Valentina, Yang, Xiaoxu, Ross, Danica, Traynor, Bryan J, Alhashem, Amal M, Azam, Matloob, Selim, Laila, Bastaki, Laila, Elbastawisy, Hanan I, Temtamy, Samia, Zaki, Maha, and Gleeson, Joseph G
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Biochemistry and Cell Biology ,Bioinformatics and Computational Biology ,Genetics ,Biological Sciences ,Intellectual and Developmental Disabilities (IDD) ,Pediatric ,Neurosciences ,Brain Disorders ,Congenital Structural Anomalies ,Clinical Research ,Human Genome ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Amino Acid Sequence ,Child ,Child ,Preschool ,Consanguinity ,Endoplasmic Reticulum ,Exons ,Female ,Genetic Predisposition to Disease ,Homozygote ,Humans ,Male ,Membrane Proteins ,Microcephaly ,Mutation ,Protein Disulfide-Isomerases ,Protein Folding ,Thioredoxins ,Exome Sequencing ,TMX2 ,thioredoxin ,ER stress ,microlissencephaly ,protein disulfide isomerase ,Medical and Health Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
BackgroundProtein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.MethodsEight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.ResultsAn identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72 repeat expansion toxicity, patients showed no evidence of C9ORF72 repeat expansions.ConclusionThe TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72 expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.
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- 2020
32. mTOR pathway somatic variants and the molecular pathogenesis of hemimegalencephaly
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Garcia, Camila AB, Carvalho, Simone CS, Yang, Xiaoxu, Ball, Laurel L, George, Renee D, James, Kiely N, Stanley, Valentina, Breuss, Martin W, Thomé, Ursula, Santos, Marcelo V, Saggioro, Fabiano P, Serafini, Luciano Neder, Silva, Wilson A, Gleeson, Joseph G, and Machado, Hélio R
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Genetics ,Biotechnology ,Brain Disorders ,Pediatric ,Underpinning research ,1.1 Normal biological development and functioning ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,epilepsy ,hemimegalencephaly ,mTOR ,Clinical sciences ,Biological psychology - Abstract
ObjectivesRecently, defects in the protein kinase mTOR (mammalian target of rapamycin) and its associated pathway have been correlated with hemimegalencephaly (HME). mTOR acts as a central regulator of important physiological cellular functions such as growth and proliferation, metabolism, autophagy, death, and survival. This study was aimed at identifying specific variants in mTOR signaling pathway genes in patients diagnosed with HME.MethodsUsing amplicon and whole exome sequencing (WES) of resected brain and paired blood samples from five HME patients, we were able to identify pathogenic mosaic variants in the mTOR pathway genes MTOR, PIK3CA, and DEPDC5.ResultsThese results strengthen the hypothesis that somatic variants in PI3K-Akt-mTOR pathway genes contribute to HME. We also describe one patient presenting with a pathogenic variant on DEPDC5 gene, which reinforces the role of DEPDC5 on cortical structural changes due to mTORC1 hyperactivation. These findings also provide insights into when in brain development these variants occurred. An early developmental variant is expected to affect a larger number of cells and to result in a larger malformation, whereas the same variant occurring later in development would cause a minor malformation.SignificanceIn the future, numerous somatic variants in known or new genes will undoubtedly be revealed in resected brain samples, making it possible to draw correlations between genotypes and phenotypes and allow for a genetic clinical diagnosis that may help to predict a given patient's outcome.
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- 2020
33. Autism risk in offspring can be assessed through quantification of male sperm mosaicism
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Breuss, Martin W, Antaki, Danny, George, Renee D, Kleiber, Morgan, James, Kiely N, Ball, Laurel L, Hong, Oanh, Mitra, Ileena, Yang, Xiaoxu, Wirth, Sara A, Gu, Jing, Garcia, Camila AB, Gujral, Madhusudan, Brandler, William M, Musaev, Damir, Nguyen, An, McEvoy-Venneri, Jennifer, Knox, Renatta, Sticca, Evan, Botello, Martha Cristina Cancino, Uribe Fenner, Javiera, Pérez, Maria Cárcel, Arranz, Maria, Moffitt, Andrea B, Wang, Zihua, Hervás, Amaia, Devinsky, Orrin, Gymrek, Melissa, Sebat, Jonathan, and Gleeson, Joseph G
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Biomedical and Clinical Sciences ,Mental Health ,Serious Mental Illness ,Autism ,Intellectual and Developmental Disabilities (IDD) ,Genetics ,Human Genome ,Pediatric ,Brain Disorders ,Contraception/Reproduction ,2.1 Biological and endogenous factors ,Aetiology ,Autistic Disorder ,Female ,Genetic Predisposition to Disease ,Humans ,Male ,Mosaicism ,Mutation ,Pedigree ,Polymorphism ,Single Nucleotide ,Recurrence ,Risk Factors ,Spermatozoa ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - Abstract
De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.
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- 2020
34. Somatic double-hit in MTOR and RPS6 in hemimegalencephaly with intractable epilepsy
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Pelorosso, Cristiana, Watrin, Françoise, Conti, Valerio, Buhler, Emmanuelle, Gelot, Antoinette, Yang, Xiaoxu, Mei, Davide, McEvoy-Venneri, Jennifer, Manent, Jean-Bernard, Cetica, Valentina, Ball, Laurel L, Buccoliero, Anna Maria, Vinck, Antonin, Barba, Carmen, Gleeson, Joseph G, Guerrini, Renzo, and Represa, Alfonso
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Rare Diseases ,Neurosciences ,Epilepsy ,Genetics ,Neurodegenerative ,Tuberous Sclerosis ,Brain Disorders ,Pediatric ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Brain ,Child ,Drug Resistant Epilepsy ,Female ,Hemimegalencephaly ,Humans ,Malformations of Cortical Development ,Malformations of Cortical Development ,Group I ,Mice ,Mosaicism ,Mutation ,Neurons ,Ribosomal Protein S6 ,TOR Serine-Threonine Kinases ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
Single germline or somatic activating mutations of mammalian target of rapamycin (mTOR) pathway genes are emerging as a major cause of type II focal cortical dysplasia (FCD), hemimegalencephaly (HME) and tuberous sclerosis complex (TSC). A double-hit mechanism, based on a primary germline mutation in one allele and a secondary somatic hit affecting the other allele of the same gene in a small number of cells, has been documented in some patients with TSC or FCD. In a patient with HME, severe intellectual disability, intractable seizures and hypochromic skin patches, we identified the ribosomal protein S6 (RPS6) p.R232H variant, present as somatic mosaicism at ~15.1% in dysplastic brain tissue and ~11% in blood, and the MTOR p.S2215F variant, detected as ~8.8% mosaicism in brain tissue, but not in blood. Overexpressing the two variants independently in animal models, we demonstrated that MTOR p.S2215F caused neuronal migration delay and cytomegaly, while RPS6 p.R232H prompted increased cell proliferation. Double mutants exhibited a more severe phenotype, with increased proliferation and migration defects at embryonic stage and, at postnatal stage, cytomegalic cells exhibiting eccentric nuclei and binucleation, which are typical features of balloon cells. These findings suggest a synergistic effect of the two variants. This study indicates that, in addition to single activating mutations and double-hit inactivating mutations in mTOR pathway genes, severe forms of cortical dysplasia can also result from activating mutations affecting different genes in this pathway. RPS6 is a potential novel disease-related gene.
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- 2019
35. Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay
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Lee, Sangmoon, Chen, Dillon Y, Zaki, Maha S, Maroofian, Reza, Houlden, Henry, Di Donato, Nataliya, Abdin, Dalia, Morsy, Heba, Mirzaa, Ghayda M, Dobyns, William B, McEvoy-Venneri, Jennifer, Stanley, Valentina, James, Kiely N, Mancini, Grazia MS, Schot, Rachel, Kalayci, Tugba, Altunoglu, Umut, Karimiani, Ehsan Ghayoor, Brick, Lauren, Kozenko, Mariya, Jamshidi, Yalda, Manzini, M Chiara, Toosi, Mehran Beiraghi, and Gleeson, Joseph G
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Biological Sciences ,Neurosciences ,Intellectual and Developmental Disabilities (IDD) ,Brain Disorders ,Neurological ,Alleles ,Classical Lissencephalies and Subcortical Band Heterotopias ,Cytoskeletal Proteins ,Developmental Disabilities ,Female ,Humans ,Lissencephaly ,Male ,Pedigree ,APC2 ,agyria ,band heterotopia ,epilepsy ,intellectual disability ,lissencephaly ,neuronal migration ,pachygyria ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as α-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.
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- 2019
36. Reversibility and developmental neuropathology of linear nevus sebaceous syndrome caused by dysregulation of the RAS pathway
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Kim, Ye Eun, Kim, Yong-Seok, Lee, Hee-Eun, So, Ki Hurn, Choe, Youngshik, Suh, Byung-Chang, Kim, Joung-Hun, Park, Sang Ki, Mathern, Gary W., Gleeson, Joseph G., Rah, Jong-Cheol, and Baek, Seung Tae
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- 2023
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37. Biallelic BICD2 variant is a novel candidate for Cohen-like syndrome
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Caglayan, Ahmet Okay, Tuysuz, Beyhan, Gül, Ece, Alkaya, Dilek Uludag, Yalcinkaya, Cengiz, Gleeson, Joseph G., Bilguvar, Kaya, and Gunel, Murat
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- 2022
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38. Genome Sequencing for Diagnosing Rare Diseases
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Wojcik, Monica H., primary, Lemire, Gabrielle, additional, Berger, Eva, additional, Zaki, Maha S., additional, Wissmann, Mariel, additional, Win, Wathone, additional, White, Susan M., additional, Weisburd, Ben, additional, Wieczorek, Dagmar, additional, Waddell, Leigh B., additional, Verboon, Jeffrey M., additional, VanNoy, Grace E., additional, Töpf, Ana, additional, Tan, Tiong Yang, additional, Syrbe, Steffen, additional, Strehlow, Vincent, additional, Straub, Volker, additional, Stenton, Sarah L., additional, Snow, Hana, additional, Singer-Berk, Moriel, additional, Silver, Josh, additional, Shril, Shirlee, additional, Seaby, Eleanor G., additional, Schneider, Ronen, additional, Sankaran, Vijay G., additional, Sanchis-Juan, Alba, additional, Russell, Kathryn A., additional, Reinson, Karit, additional, Ravenscroft, Gianina, additional, Radtke, Maximilian, additional, Popp, Denny, additional, Polster, Tilman, additional, Platzer, Konrad, additional, Pierce, Eric A., additional, Place, Emily M., additional, Pajusalu, Sander, additional, Pais, Lynn, additional, Õunap, Katrin, additional, Osei-Owusu, Ikeoluwa, additional, Opperman, Henry, additional, Okur, Volkan, additional, Oja, Kaisa Teele, additional, O’Leary, Melanie, additional, O’Heir, Emily, additional, Morel, Chantal F., additional, Merkenschlager, Andreas, additional, Marchant, Rhett G., additional, Mangilog, Brian E., additional, Madden, Jill A., additional, MacArthur, Daniel, additional, Lovgren, Alysia, additional, Lerner-Ellis, Jordan P., additional, Lin, Jasmine, additional, Laing, Nigel, additional, Hildebrandt, Friedhelm, additional, Hentschel, Julia, additional, Groopman, Emily, additional, Goodrich, Julia, additional, Gleeson, Joseph G., additional, Ghaoui, Roula, additional, Genetti, Casie A., additional, Gburek-Augustat, Janina, additional, Gazda, Hanna T., additional, Ganesh, Vijay S., additional, Ganapathi, Mythily, additional, Gallacher, Lyndon, additional, Fu, Jack M., additional, Evangelista, Emily, additional, England, Eleina, additional, Donkervoort, Sandra, additional, DiTroia, Stephanie, additional, Cooper, Sandra T., additional, Chung, Wendy K., additional, Christodoulou, John, additional, Chao, Katherine R., additional, Cato, Liam D., additional, Bujakowska, Kinga M., additional, Bryen, Samantha J., additional, Brand, Harrison, additional, Bönnemann, Carsten G., additional, Beggs, Alan H., additional, Baxter, Samantha M., additional, Bartolomaeus, Tobias, additional, Agrawal, Pankaj B., additional, Talkowski, Michael, additional, Austin-Tse, Christina, additional, Abou Jamra, Rami, additional, Rehm, Heidi L., additional, and O’Donnell-Luria, Anne, additional
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- 2024
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39. Evaluating human mutation databases for “treatability” using patient-customized therapy
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Mittal, Swapnil, Tang, Isaac, and Gleeson, Joseph G.
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- 2022
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40. Personalized antisense oligonucleotides ‘for free, for life’ — the n-Lorem Foundation
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Gleeson, Joseph G., Bennett, C. Frank, Carroll, Jeffrey B., Cole, Tracy, Douville, Julie, Glass, Sarah, Tekendo-Ngongang, Cedrik, Williford, Amy C., and Crooke, Stanley T.
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- 2023
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41. Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors
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Li, Hongda, Saucedo-Cuevas, Laura, Yuan, Ling, Ross, Danica, Johansen, Anide, Sands, Daniel, Stanley, Valentina, Guemez-Gamboa, Alicia, Gregor, Anne, Evans, Todd, Chen, Shuibing, Tan, Lei, Molina, Henrik, Sheets, Nicholas, Shiryaev, Sergey A, Terskikh, Alexey V, Gladfelter, Amy S, Shresta, Sujan, Xu, Zhiheng, and Gleeson, Joseph G
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Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Stem Cell Research ,Infectious Diseases ,Good Health and Well Being ,Apoptosis ,Cytokinesis ,Cytoskeleton ,HEK293 Cells ,HeLa Cells ,Humans ,Mitosis ,Neural Stem Cells ,Neurogenesis ,RNA Helicases ,Septins ,Serine Endopeptidases ,Viral Nonstructural Proteins ,Zika Virus ,Hela Cells ,Zika ,activated caspase ,cytokinesis ,microcephaly ,protease ,septin ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Zika virus (ZIKV) targets neural progenitor cells in the brain, attenuates cell proliferation, and leads to cell death. Here, we describe a role for the ZIKV protease NS2B-NS3 heterodimer in mediating neurotoxicity through cleavage of a host protein required for neurogenesis. Similar to ZIKV infection, NS2B-NS3 expression led to cytokinesis defects and cell death in a protease activity-dependent fashion. Among binding partners, NS2B-NS3 cleaved Septin-2, a cytoskeletal factor involved in cytokinesis. Cleavage of Septin-2 occurred at residue 306 and forced expression of a non-cleavable Septin-2 restored cytokinesis, suggesting a direct mechanism of ZIKV-induced neural toxicity. VIDEO ABSTRACT.
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- 2019
42. Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.
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Friedman, Jennifer, Smith, Desiree E, Issa, Mahmoud Y, Stanley, Valentina, Wang, Rengang, Mendes, Marisa I, Wright, Meredith S, Wigby, Kristen, Hildreth, Amber, Crawford, John R, Koehler, Alanna E, Chowdhury, Shimul, Nahas, Shareef, Zhai, Liting, Xu, Zhiwen, Lo, Wing-Sze, James, Kiely N, Musaev, Damir, Accogli, Andrea, Guerrero, Kether, Tran, Luan T, Omar, Tarek EI, Ben-Omran, Tawfeg, Dimmock, David, Kingsmore, Stephen F, Salomons, Gajja S, Zaki, Maha S, Bernard, Geneviève, and Gleeson, Joseph G
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Humans ,Microcephaly ,Epilepsy ,Disease Progression ,Genetic Predisposition to Disease ,Valine-tRNA Ligase ,RNA ,Transfer ,Anticodon ,Longitudinal Studies ,Pedigree ,Protein Biosynthesis ,Mutation ,Alleles ,Models ,Molecular ,Child ,Child ,Preschool ,Female ,Male ,Protein Interaction Domains and Motifs ,Neurodevelopmental Disorders ,Whole Genome Sequencing ,Whole Exome Sequencing ,Loss of Function Mutation ,Neurodegenerative ,Intellectual and Developmental Disabilities (IDD) ,Pediatric ,Rare Diseases ,Genetics ,Neurosciences ,Brain Disorders ,2.1 Biological and endogenous factors - Abstract
Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.
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- 2019
43. Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications
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Rosenhahn, Erik, O’Brien, Thomas J., Zaki, Maha S., Sorge, Ina, Wieczorek, Dagmar, Rostasy, Kevin, Vitobello, Antonio, Nambot, Sophie, Alkuraya, Fowzan S., Hashem, Mais O., Alhashem, Amal, Tabarki, Brahim, Alamri, Abdullah S., Al Safar, Ayat H., Bubshait, Dalal K., Alahmady, Nada F., Gleeson, Joseph G., Abdel-Hamid, Mohamed S., Lesko, Nicole, Ygberg, Sofia, Correia, Sandrina P., Wredenberg, Anna, Alavi, Shahryar, Seyedhassani, Seyed M., Ebrahimi Nasab, Mahya, Hussien, Haytham, Omar, Tarek E.I., Harzallah, Ines, Touraine, Renaud, Tajsharghi, Homa, Morsy, Heba, Houlden, Henry, Shahrooei, Mohammad, Ghavideldarestani, Maryam, Abdel-Salam, Ghada M.H., Torella, Annalaura, Zanobio, Mariateresa, Terrone, Gaetano, Brunetti-Pierri, Nicola, Omrani, Abdolmajid, Hentschel, Julia, Lemke, Johannes R., Sticht, Heinrich, Abou Jamra, Rami, Brown, Andre E.X., Maroofian, Reza, and Platzer, Konrad
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- 2022
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44. Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder
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Kumar, Raman, Corbett, Mark A., Smith, Nicholas J. C., Hock, Daniella H., Kikhtyak, Zoya, Semcesen, Liana N., Morimoto, Atsushi, Lee, Sangmoon, Stroud, David A., Gleeson, Joseph G., Haan, Eric A., and Gecz, Jozef
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- 2022
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45. Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance
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Rapaport, Franck, Boisson, Bertrand, Gregor, Anne, Béziat, Vivien, Boisson-Dupuis, Stéphanie, Bustamante, Jacinta, Jouanguy, Emmanuelle, Puel, Anne, Rosain, Jérémie, Zhang, Qian, Zhang, Shen-Ying, Gleeson, Joseph G., Quintana-Murci, Lluis, Casanova, Jean-Laurent, Abel, Laurent, and Patin, Etienne
- Published
- 2021
46. Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome
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Ghosh, Shereen G, Becker, Kerstin, Huang, He, Dixon-Salazar, Tracy, Chai, Guoliang, Salpietro, Vincenzo, Al-Gazali, Lihadh, Waisfisz, Quinten, Wang, Haicui, Vaux, Keith K, Stanley, Valentina, Manole, Andreea, Akpulat, Ugur, Weiss, Marjan M, Efthymiou, Stephanie, Hanna, Michael G, Minetti, Carlo, Striano, Pasquale, Pisciotta, Livia, De Grandis, Elisa, Altmüller, Janine, Weixler, Lisa, Nürnberg, Peter, Thiele, Holger, Yis, Uluc, Okur, Tuncay Derya, Polat, Ayse Ipek, Amiri, Nafise, Doosti, Mohammad, Karimani, Ehsan Ghayoor, Toosi, Mehran B, Haddad, Gabriel, Karakaya, Mert, Wirth, Brunhilde, van Hagen, Johanna M, Wolf, Nicole I, Maroofian, Reza, Houlden, Henry, Cirak, Sebahattin, and Gleeson, Joseph G
- Subjects
Biochemistry and Cell Biology ,Genetics ,Biological Sciences ,Epilepsy ,Pediatric ,Brain Disorders ,Neurosciences ,Rare Diseases ,Neurodegenerative ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,ADP-ribosylation ,ADPRHL2 ,ARH3 ,SUDEP ,ataxia ,epilepsy ,neurodegeneration ,neuropathy ,oxidative stress ,poly-ADP ribose ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.
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- 2018
47. Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome
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Breuss, Martin W, Nguyen, An, Song, Qiong, Nguyen, Thai, Stanley, Valentina, James, Kiely N, Musaev, Damir, Chai, Guoliang, Wirth, Sara A, Anzenberg, Paula, George, Renee D, Johansen, Anide, Ali, Shaila, Zia-ur-Rehman, Muhammad, Sultan, Tipu, Zaki, Maha S, and Gleeson, Joseph G
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Biological Sciences ,Bioinformatics and Computational Biology ,Neurosciences ,Brain Disorders ,Genetics ,Pediatric ,Clinical Research ,Intellectual and Developmental Disabilities (IDD) ,Neurodegenerative ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adolescent ,Animals ,Atrophy ,Cell Differentiation ,Child ,Corpus Callosum ,Endoplasmic Reticulum ,Female ,Homeodomain Proteins ,Humans ,Infant ,Intellectual Disability ,Male ,Membrane Proteins ,Mice ,Muscle Hypotonia ,Mutation ,Phenotype ,Psychomotor Disorders ,Stem Cells ,KIAA1715 ,corpus callosum hypoplasia ,endoplasmic reticulum ,epilepsy ,human genetics ,hypotonia ,lunapark ,organelle morphology ,recessive disease ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
The dynamic shape of the endoplasmic reticulum (ER) is a reflection of its wide variety of critical cell biological functions. Consequently, perturbation of ER-shaping proteins can cause a range of human phenotypes. Here, we describe three affected children (from two consanguineous families) who carry homozygous loss-of-function mutations in LNPK (previously known as KIAA1715); this gene encodes lunapark, which is proposed to serve as a curvature-stabilizing protein within tubular three-way junctions of the ER. All individuals presented with severe psychomotor delay, intellectual disability, hypotonia, epilepsy, and corpus callosum hypoplasia, and two of three showed mild cerebellar hypoplasia and atrophy. Consistent with a proposed role in neurodevelopmental disease, LNPK was expressed during brain development in humans and mice and was present in neurite-like processes in differentiating human neural progenitor cells. Affected cells showed the absence of full-length lunapark, aberrant ER structures, and increased luminal mass density. Together, our results implicate the ER junction stabilizer lunapark in establishing the corpus callosum.
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- 2018
48. Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.
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Schaffer, Ashleigh E, Breuss, Martin W, Caglayan, Ahmet Okay, Al-Sanaa, Nouriya, Al-Abdulwahed, Hind Y, Kaymakçalan, Hande, Yılmaz, Cahide, Zaki, Maha S, Rosti, Rasim O, Copeland, Brett, Baek, Seung Tae, Musaev, Damir, Scott, Eric C, Ben-Omran, Tawfeg, Kariminejad, Ariana, Kayserili, Hulya, Mojahedi, Faezeh, Kara, Majdi, Cai, Na, Silhavy, Jennifer L, Elsharif, Seham, Fenercioglu, Elif, Barshop, Bruce A, Kara, Bulent, Wang, Rengang, Stanley, Valentina, James, Kiely N, Nachnani, Rahul, Kalur, Aneesha, Megahed, Hisham, Incecik, Faruk, Danda, Sumita, Alanay, Yasemin, Faqeih, Eissa, Melikishvili, Gia, Mansour, Lobna, Miller, Ian, Sukhudyan, Biayna, Chelly, Jamel, Dobyns, William B, Bilguvar, Kaya, Jamra, Rami Abou, Gunel, Murat, and Gleeson, Joseph G
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Cerebral Cortex ,Neurons ,Animals ,Mice ,Inbred C57BL ,Humans ,Mice ,Nerve Tissue Proteins ,Pedigree ,Cell Movement ,Mutation ,Genome ,Human ,alpha Catenin ,Actin-Related Protein 2-3 Complex ,Embryo ,Mammalian ,Neurosciences ,Rare Diseases ,Clinical Research ,2.1 Biological and endogenous factors ,Neurological ,Developmental Biology ,Biological Sciences ,Medical and Health Sciences - Abstract
Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between β-catenin and Arp2/3 actin filament activities1. Loss of αN-catenin did not affect β-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.
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- 2018
49. Paternally inherited cis-regulatory structural variants are associated with autism
- Author
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Brandler, William M, Antaki, Danny, Gujral, Madhusudan, Kleiber, Morgan L, Whitney, Joe, Maile, Michelle S, Hong, Oanh, Chapman, Timothy R, Tan, Shirley, Tandon, Prateek, Pang, Timothy, Tang, Shih C, Vaux, Keith K, Yang, Yan, Harrington, Eoghan, Juul, Sissel, Turner, Daniel J, Thiruvahindrapuram, Bhooma, Kaur, Gaganjot, Wang, Zhuozhi, Kingsmore, Stephen F, Gleeson, Joseph G, Bisson, Denis, Kakaradov, Boyko, Telenti, Amalio, Venter, J Craig, Corominas, Roser, Toma, Claudio, Cormand, Bru, Rueda, Isabel, Guijarro, Silvina, Messer, Karen S, Nievergelt, Caroline M, Arranz, Maria J, Courchesne, Eric, Pierce, Karen, Muotri, Alysson R, Iakoucheva, Lilia M, Hervas, Amaia, Scherer, Stephen W, Corsello, Christina, and Sebat, Jonathan
- Subjects
Genetics ,Intellectual and Developmental Disabilities (IDD) ,Pediatric ,Clinical Research ,Congenital Structural Anomalies ,Autism ,Brain Disorders ,Mental Health ,Aetiology ,2.1 Biological and endogenous factors ,Autism Spectrum Disorder ,Exons ,Gene Expression Regulation ,Genetic Predisposition to Disease ,Genetic Variation ,Genome ,Human ,Humans ,Mutation ,Paternal Inheritance ,Pedigree ,Promoter Regions ,Genetic ,RNA ,Untranslated ,Selection ,Genetic ,Sequence Deletion ,Transcription Factors ,General Science & Technology - Abstract
The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.
- Published
- 2018
50. Defining the phenotypic spectrum of SLC6A1 mutations
- Author
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Johannesen, Katrine M, Gardella, Elena, Linnankivi, Tarja, Courage, Carolina, Martin, Anne Saint, Lehesjoki, Anna‐Elina, Mignot, Cyril, Afenjar, Alexandra, Lesca, Gaetan, Abi‐Warde, Marie‐Thérèse, Chelly, Jamel, Piton, Amélie, Merritt, J Lawrence, Rodan, Lance H, Tan, Wen‐Hann, Bird, Lynne M, Nespeca, Mark, Gleeson, Joseph G, Yoo, Yongjin, Choi, Murim, Chae, Jong‐Hee, Czapansky‐Beilman, Desiree, Reichert, Sara Chadwick, Pendziwiat, Manuela, Verhoeven, Judith S, Schelhaas, Helenius J, Devinsky, Orrin, Christensen, Jakob, Specchio, Nicola, Trivisano, Marina, Weber, Yvonne G, Nava, Caroline, Keren, Boris, Doummar, Diane, Schaefer, Elise, Hopkins, Sarah, Dubbs, Holly, Shaw, Jessica E, Pisani, Laura, Myers, Candace T, Tang, Sha, Tang, Shan, Pal, Deb K, Millichap, John J, Carvill, Gemma L, Helbig, Kathrine L, Mecarelli, Oriano, Striano, Pasquale, Helbig, Ingo, Rubboli, Guido, Mefford, Heather C, and Møller, Rikke S
- Subjects
Behavioral and Social Science ,Neurodegenerative ,Neurosciences ,Genetics ,Epilepsy ,Clinical Research ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adolescent ,Adult ,Anticonvulsants ,Ataxia ,Child ,Child ,Preschool ,Cohort Studies ,Electroencephalography ,Epilepsies ,Myoclonic ,Epilepsies ,Partial ,Epilepsy ,Generalized ,Female ,GABA Plasma Membrane Transport Proteins ,Genetic Association Studies ,Humans ,Intellectual Disability ,Language Development Disorders ,Male ,Mutation ,Mutation ,Missense ,Neurodevelopmental Disorders ,Phenotype ,Treatment Outcome ,Valproic Acid ,Young Adult ,epilepsy ,epilepsy genetics ,MAE ,SLC6A1 ,MAE ,SLC6A1 ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
ObjectivePathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients.MethodsWe collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects.ResultsCognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg).SignificanceMost patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.
- Published
- 2018
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