المؤلفون: Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra, Jan-Ulrich Schlump, Desiree DeMille, Pinar Bayrak-Toydemir, Gary Rex Nelson, Kristen Nicole Wong, Laura Duncan, Mackenzie Mosera, Christian Gilissen, Lisenka E. L. M. Vissers, Rolph Pfundt, Rogier Kersseboom, Hilde Yttervik, Geir Åsmund Myge Hansen, Marie Falkenberg Smeland, Kameryn M. Butler, Michael J. Lyons, Claudia M. B. Carvalho, Chaofan Zhang, James R. Lupski, Lorraine Potocki, Leticia Flores-Gallegos, Rodrigo Morales-Toquero, Florence Petit, Binnaz Yalcin, Annabelle Tuttle, Houda Zghal Elloumi, Lane McCormick, Mary Kukolich, Oliver Klaas, Judit Horvath, Marcello Scala, Michele Iacomino, Francesca Operto, Federico Zara, Karin Writzl, Aleš Maver, Maria K. Haanpää, Pia Pohjola, Harri Arikka, Anneke J. A. Kievit, Camilla Calandrini, Christian Iseli, Nicolas Guex, Alexandre Reymond

المصدر: Genome Medicine, Vol 16, Iss 1, Pp 1-18 (2024)

مصطلحات موضوعية: Mesomelic dysplasia, Horseshoe kidney, Intellectual disability, Transcriptome, Zebrafish model, Medicine, Genetics, QH426-470

الوصف: Abstract Background We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. Methods Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1756-994XTest

الوصول الحر: https://doaj.org/article/0358fc56f6054b188a138c71c996e968Test

المؤلفون: Carolina Gracia-Diaz, Yijing Zhou, Qian Yang, Reza Maroofian, Paula Espana-Bonilla, Chul-Hwan Lee, Shuo Zhang, Natàlia Padilla, Raquel Fueyo, Elisa A. Waxman, Sunyimeng Lei, Garrett Otrimski, Dong Li, Sarah E. Sheppard, Paul Mark, Margaret H. Harr, Hakon Hakonarson, Lance Rodan, Adam Jackson, Pradeep Vasudevan, Corrina Powel, Shehla Mohammed, Sateesh Maddirevula, Hamad Alzaidan, Eissa A. Faqeih, Stephanie Efthymiou, Valentina Turchetti, Fatima Rahman, Shazia Maqbool, Vincenzo Salpietro, Shahnaz H. Ibrahim, Gabriella di Rosa, Henry Houlden, Maha Nasser Alharbi, Nouriya Abbas Al-Sannaa, Peter Bauer, Giovanni Zifarelli, Conchi Estaras, Anna C. E. Hurst, Michelle L. Thompson, Anna Chassevent, Constance L. Smith-Hicks, Xavier de la Cruz, Alexander M. Holtz, Houda Zghal Elloumi, M J Hajianpour, Claudine Rieubland, Dominique Braun, Siddharth Banka, Genomic England Research Consortium, Deborah L. French, Elizabeth A. Heller, Murielle Saade, Hongjun Song, Guo-li Ming, Fowzan S. Alkuraya, Pankaj B. Agrawal, Danny Reinberg, Elizabeth J. Bhoj, Marian A. Martínez-Balbás, Naiara Akizu

المصدر: Nature Communications, Vol 14, Iss 1, Pp 1-18 (2023)

مصطلحات موضوعية: Science

الوصف: Abstract Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/78105606e072432f9749da08dbbd20b7Test

المؤلفون: Rauan Kaiyrzhanov, Maha S. Zaki, Tracy Lau, Sambuddha Sen, Reza Azizimalamiri, Mina Zamani, Gözde Yeşil Sayin, Taru Hilander, Stephanie Efthymiou, Viorica Chelban, Ruth Brown, Kyle Thompson, Maria Irene Scarano, Jaya Ganesh, Kairgali Koneev, Ismail Musab Gülaçar, Richard Person, Dinara Sadykova, Yerdan Maidyrov, Tahereh Seifi, Aizhan Zadagali, Geneviève Bernard, Katrina Allis, Houda Zghal Elloumi, Amanda Lindy, Ehsan Taghiabadi, Sumit Verma, Rachel Logan, Brian Kirmse, Renkui Bai, Shaimaa M. Khalaf, Mohamed S. Abdel‐Hamid, Alireza Sedaghat, Gholamreza Shariati, Mahmoud Issa, Jawaher Zeighami, Hasnaa M. Elbendary, Garry Brown, Robert W. Taylor, Hamid Galehdari, Joseph J. Gleeson, Christopher J. Carroll, James A. Cowan, Andres Moreno‐De‐Luca, Henry Houlden, Reza Maroofian

المصدر: Annals of Clinical and Translational Neurology, Vol 9, Iss 12, Pp 2025-2035 (2022)

مصطلحات موضوعية: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429

الوصف: Abstract Bi‐allelic variants in Iron–Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early‐onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra‐rare bi‐allelic NFU1 missense variants associated with a spectrum of early‐onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1‐related phenotypic continuum.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2328-9503Test

الوصول الحر: https://doaj.org/article/711cfaa4bbdd40c88cf90df5e876adc6Test

المؤلفون: Ulrike Hüffmeier, Cornelia Kraus, Miriam S. Reuter, Steffen Uebe, Mary-Alice Abbott, Syed A. Ahmed, Kristyn L. Rawson, Eileen Barr, Hong Li, Ange-Line Bruel, Laurence Faivre, Frédéric Tran Mau-Them, Christina Botti, Susan Brooks, Kaitlyn Burns, D. Isum Ward, Marina Dutra-Clarke, Julian A. Martinez-Agosto, Hane Lee, Stanley F. Nelson, UCLA California Center for Rare Disease, Pia Zacher, Rami Abou Jamra, Chiara Klöckner, Julie McGaughran, Jürgen Kohlhase, Sarah Schuhmann, Ellen Moran, John Pappas, Annick Raas-Rothschild, Maria J. Guillen Sacoto, Lindsay B. Henderson, Timothy Blake Palculict, Sureni V. Mullegama, Houda Zghal Elloumi, Adi Reich, Samantha A. Schrier Vergano, Erica Wahl, André Reis, Christiane Zweier

المصدر: Orphanet Journal of Rare Diseases, Vol 16, Iss 1, Pp 1-9 (2021)

مصطلحات موضوعية: EIF3F gene, Neurodevelopmental disorder, Short stature, Deafness, Behavioral difficulties, Altered muscular tone, Medicine

الوصف: Abstract Background An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients. Results 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals’ facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype–phenotype correlation. Conclusions Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1750-1172Test

الوصول الحر: https://doaj.org/article/8bc14e835d25412b97b23f80259be0cfTest

المؤلفون: Susan M. Hiatt, Slavica Trajkova, Matteo Rossi Sebastiano, E. Christopher Partridge, Fatima E. Abidi, Ashlyn Anderson, Muhammad Ansar, Stylianos E. Antonarakis, Azadeh Azadi, Ruxandra Bachmann-Gagescu, Andrea Bartuli, Caroline Benech, Jennifer L. Berkowitz, Michael J. Betti, Alfredo Brusco, Ashley Cannon, Giulia Caron, Yanmin Chen, Meagan E. Cochran, Tanner F. Coleman, Molly M. Crenshaw, Laurence Cuisset, Cynthia J. Curry, Hossein Darvish, Serwet Demirdas, Maria Descartes, Jessica Douglas, David A. Dyment, Houda Zghal Elloumi, Giuseppe Ermondi, Marie Faoucher, Emily G. Farrow, Stephanie A. Felker, Heather Fisher, Anna C.E. Hurst, Pascal Joset, Melissa A. Kelly, Stanislav Kmoch, Benjamin R. Leadem, Michael J. Lyons, Marina Macchiaiolo, Martin Magner, Giorgia Mandrile, Francesca Mattioli, Megan McEown, Sarah K. Meadows, Livija Medne, Naomi J.L. Meeks, Sarah Montgomery, Melanie P. Napier, Marvin Natowicz, Kimberly M. Newberry, Marcello Niceta, Lenka Noskova, Catherine B. Nowak, Amanda G. Noyes, Matthew Osmond, Eloise J. Prijoles, Jada Pugh, Verdiana Pullano, Chloé Quélin, Simin Rahimi-Aliabadi, Anita Rauch, Sylvia Redon, Alexandre Reymond, Caitlin R. Schwager, Elizabeth A. Sellars, Angela E. Scheuerle, Elena Shukarova-Angelovska, Cara Skraban, Elliot Stolerman, Bonnie R. Sullivan, Marco Tartaglia, Isabelle Thiffault, Kevin Uguen, Luis A. Umaña, Yolande van Bever, Saskia N. van der Crabben, Marjon A. van Slegtenhorst, Quinten Waisfisz, Camerun Washington, Lance H. Rodan, Richard M. Myers, Gregory M. Cooper

المساهمون: Human Genetics, Amsterdam Cardiovascular Sciences, Human genetics, CCA - Cancer biology and immunology, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Clinical Genetics

المصدر: American journal of human genetics, 110(2), 215-227. Cell Press
Hiatt, S M, Trajkova, S, Sebastiano, M R, Partridge, E C, Abidi, F E, Anderson, A, Ansar, M, Antonarakis, S E, Azadi, A, Bachmann-Gagescu, R, Bartuli, A, Benech, C, Berkowitz, J L, Betti, M J, Brusco, A, Cannon, A, Caron, G, Chen, Y, Cochran, M E, Coleman, T F, Crenshaw, M M, Cuisset, L, Curry, C J, Darvish, H, Demirdas, S, Descartes, M, Douglas, J, Dyment, D A, Elloumi, H Z, Ermondi, G, Faoucher, M, Farrow, E G, Felker, S A, Fisher, H, Hurst, A C E, Joset, P, Kelly, M A, Kmoch, S, Leadem, B R, Lyons, M J, Macchiaiolo, M, Magner, M, Mandrile, G, Mattioli, F, McEown, M, Meadows, S K, Medne, L, Meeks, N J L, Montgomery, S, Napier, M P, Natowicz, M, Newberry, K M, Niceta, M, Noskova, L, Nowak, C B, Noyes, A G, Osmond, M, Prijoles, E J, Pugh, J, Pullano, V, Quélin, C, Rahimi-Aliabadi, S, Rauch, A, Redon, S, Reymond, A, Schwager, C R, Sellars, E A, Scheuerle, A E, Shukarova-Angelovska, E, Skraban, C, Stolerman, E, Sullivan, B R, Tartaglia, M, Thiffault, I, Uguen, K, Umaña, L A, van Bever, Y, van der Crabben, S N, van Slegtenhorst, M A, Waisfisz, Q, Washington, C, Rodan, L H, Myers, R M & Cooper, G M 2023, ' Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype ', American journal of human genetics, vol. 110, no. 2, pp. 215-227 . https://doi.org/10.1016/j.ajhg.2022.12.007Test
American Journal of Human Genetics
American Journal of Human Genetics, 2023, 110 (2), pp.215-227. ⟨10.1016/j.ajhg.2022.12.007⟩
American Journal of Human Genetics, 110(2), 215-227. Cell Press

مصطلحات موضوعية: [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, ZMYM3, transcriptional coregulators, MESH: Phenotype, MESH: Gene Expression Regulation, MESH: Nervous System Malformations, neurodevelopmental disorder, MESH: Male, MESH: Intellectual Disability, X-linked intellectual disability, chromatin modifiers, MESH: Histone Demethylases, Genetics, MESH: Female, MESH: Face, MESH: Nuclear Proteins, Genetics (clinical), MESH: Neurodevelopmental Disorders

الوصف: Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9940ea52913c5bbdc54a98d0f9168154Test
https://pure.amc.nl/en/publications/deleterious-proteinaltering-variants-in-the-transcriptional-coregulator-zmym3-in-27-individuals-with-a-neurodevelopmental-delay-phenotypeTest(b3792507-cf7f-4240-a6b2-5cc40fd0a55c).html

المؤلفون: Ella F. Whittle, Madison Chilian, Ehsan Ghayoor Karimiani, Helga Progri, Daniela Buhas, Melis Kose, Rebecca D. Ganetzky, Mehran Beiraghi Toosi, Paria Najarzadeh Torbati, Reza Shervin Badv, Ivan Shelihan, Hui Yang, Houda Zghal Elloumi, Sukyeong Lee, Yalda Jamshidi, Alan M. Pittman, Henry Houlden, Erika Ignatius, Shamima Rahman, Reza Maroofian, Wan Hee Yoon, Christopher J. Carroll

المساهمون: HUS Lasten ja nuorten sairaudet, Clinicum, Lastenneurologian yksikkö

مصطلحات موضوعية: 1184 Genetiikka, kehitysbiologia, fysiologia, Ogdh, Oxoglutarate dehydrogenase, Neurodevelopmental disease, Deficiency, A-ketoglutarate dehydrogenase, Genetics (clinical), Mitochondria

الوصف: Purpose: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.Methods: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells.Results: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme alpha-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C > T:p.(Pro189Leu) and c.890C > A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G > A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells.Conclusion: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8223f73bbd5b707e1c5d859eb2bb697eTest
http://hdl.handle.net/10138/356336Test

المؤلفون: Kenneth A. Myers, Ebba Alkhunaizi, Michelle M. Morrow, Jiddeke J.P. van de Kamp, Elysa J. Marco, Suma P. Shankar, Harvey B. Sarnat, Marwan Shinawi, Jacqueline L. Steele, Megan Glassford, Colette P. DeFilippo, Tracy Brandt, Amy Waldman, Houda Zghal Elloumi, Holly Dubbs, Ganka Douglas, Sumit Parikh, Kristin G. Monaghan, Cyril Mignot, David Chitayat, Bénédicte Héron, Linda E. Kim, Farrah Rajabi, Shane C. Quinonez, William D. Graf, Mark C. Hannibal, Aravindhan Veerapandiyan

المساهمون: Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism

المصدر: Steele, J L, Morrow, M M, Sarnat, H B, Alkhunaizi, E, Brandt, T, Chitayat, D A, DeFilippo, C P, Douglas, G V, Dubbs, H A, Elloumi, H Z, Glassford, M R, Hannibal, M C, Héron, B, Kim, L E, Marco, E J, Mignot, C, Monaghan, K G, Myers, K A, Parikh, S, Quinonez, S C, Rajabi, F, Shankar, S P, Shinawi, M S, van de Kamp, J J P, Veerapandiyan, A, Waldman, A T & Graf, W D 2022, ' Semaphorin-Plexin Signaling : From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome ', Pediatric Neurology, vol. 126, pp. 65-73 . https://doi.org/10.1016/j.pediatrneurol.2021.10.008Test
Pediatric Neurology, 126, 65-73. Elsevier Inc.

مصطلحات موضوعية: Adult, Male, Adolescent, Autism Spectrum Disorder, X-linked intellectual disability, Genetic counseling, Nerve Tissue Proteins, Receptors, Cell Surface, Semaphorins, Young Adult, Neurodevelopmental disorder, Developmental Neuroscience, Semaphorin, Intellectual Disability, Intellectual disability, Humans, Medicine, Child, Genetic Association Studies, X chromosome, Genetics, biology, business.industry, Plexin, medicine.disease, Neurology, Child, Preschool, Pediatrics, Perinatology and Child Health, biology.protein, Autism, Neurology (clinical), business, Cell Adhesion Molecules, Signal Transduction

الوصف: Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05). Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da65a60f3e1ab2780a3d905dd23f1bdfTest
https://doi.org/10.1016/j.pediatrneurol.2021.10.008Test

المؤلفون: Zou Pan, Marielle E. van Gijn, Marjolein H. Willemsen, Mariet W. Elting, Susanne Koning, Daniel C. Koboldt, Rebecca Baud, Renzo Guerrini, Ghayda M. Mirzaa, Laurence E. Walsh, Kim L. McBride, Jenny Thies, Andrew E. Timms, Shaoping Huang, Gretchen E. Rosso, Joshua Scheck, Haley McConkey, Matthew A. Deardorff, Peter D. Turnpenny, Suzanne M. Leal, Sanjay M. Sisodiya, Lin Yang, Melissa Lees, Cacha M.P.C.D. Peeters-Scholte, Henry Houlden, Marielle Alders, J. Austin Hamm, Karla A. Peña-Guerra, Richard E. Person, Leena Lauronen, Hannah K. Robinson, Theresa Mihalic Mosher, Alexandra Garza-Flores, Victoria Harrison, Tuomo Määttä, Daniela Q.C.M. Barge-Schaapveld, James R. Lupski, Houda Zghal Elloumi, Francisco J. Guzmán-Vega, Tamison Jewett, Siddharth Banka, Barbara W. van Paassen, J. Lawrence Merritt, Angela Sun, Yana Lara-Taranchenko, Irma Järvelä, Ivan K. Chinn, Claudia A. L. Ruivenkamp, Nicholas M. Allen, Xiaodong Wang, Amy Crunk, Selina H. Banu, Maura R.Z. Ruzhnikov, Jeffery McGlothlin, Mashaya Zaman, Adam Jackson, Stefan T. Arold, Bert B.A. de Vries, Jing Peng, Lauren Schenck, Isabelle Schrauwen, Marjon van Slegtenhorst, Luis Alberto Pedroza, Bekim Sadikovic, Annalisa Vetro, Reshmi Ramakrishnan, Kristin G. Monaghan, Kelly J. Cardona-Londoño, Catherine Quindipan, Kristina Lanko, Rolph Pfundt, Caroline M. Kehoe, Martino Montomoli, Christian Gilissen, Hamid Galehdari, Yolande van Bever, Jennifer Keller-Ramey, Sadegheh Haghshenas, Neda Mazaheri, Stephanie Efthymiou, Reza Maroofian, Lewis Pang, Fleur Vansenne, Abeltje M. Polstra, Kara C. Klemp, Marjolein J.A. Weerts, Xi Lin, Julia Baptista, Tahsin Stefan Barakat, Anneke Kievit, Adi Reich, Stephen R. Braddock, Shehla Mohammed, Abbey M. Putnam, Jennifer Kerkhof, Matthew Pastore, Sally Ann Lynch

المساهمون: Graduate School, ANS - Neuroinfection & -inflammation, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, MUMC+: DA KG Polikliniek (9), RS: FHML non-thematic output, Human genetics, VU University medical center, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Irma Järvelä / Principal Investigator, Medicum, Department of Medical and Clinical Genetics, HUS Medical Imaging Center, Clinicum, BioMag Laboratory, HUS Children and Adolescents, Kliinisen neurofysiologian yksikkö

المصدر: Genetics in Medicine
Genetics in medicine, 23(11), 2122-2137. Lippincott Williams and Wilkins
Genetics in Medicine, 23(11), 2122-2137. SPRINGERNATURE
Genetics in Medicine, 23(11), 2122-2137. Nature Publishing Group
Genomics England Research Consortium 2021, ' Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome ', Genetics in Medicine, vol. 23, no. 11, pp. 2122-2137 . https://doi.org/10.1038/s41436-021-01246-2Test
Genetics in Medicine, 23(11), 2122-2137. Lippincott Williams and Wilkins
Genetics in Medicine, 23(11), 2122-2137. Lippincott Williams & Wilkins
Genetics in Medicine, 23, 2122-2137
Genetics in Medicine, 23, 11, pp. 2122-2137
Genomics England Research Consortium 2021, ' Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome ', Genetics in medicine : official journal of the American College of Medical Genetics . https://doi.org/10.1038/s41436-021-01246-2Test

مصطلحات موضوعية: Male, INTELLECTUAL DISABILITY, GENES, Language delay, VARIANTS, Biology, Bioinformatics, 3124 Neurology and psychiatry, Article, 12Q24.31, SETD1B, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Neurodevelopmental disorder, Seizures, Intellectual disability, medicine, Humans, MICRODELETION, Global developmental delay, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 3112 Neurosciences, RECOGNITION, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Histone-Lysine N-Methyltransferase, medicine.disease, Penetrance, Human genetics, Phenotype, Neurodevelopmental Disorders, MOTIF, Autism, METHYLTRANSFERASE, 3111 Biomedicine, 030217 neurology & neurosurgery

الوصف: Contains fulltext : 243955.pdf (Publisher’s version ) (Open Access) PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::23e4f87d1b2de6f4ec6880e740ae29d4Test
https://doi.org/10.1038/s41436-021-01246-2Test

المؤلفون: Susan M. Hiatt, Slavica Trajkova, Matteo Rossi Sebastiano, E. Christopher Partridge, Fatima E. Abidi, Ashlyn Anderson, Muhammad Ansar, Stylianos E. Antonarakis, Azadeh Azadi, Ruxandra Bachmann-Gagescu, Andrea Bartuli, Caroline Benech, Jennifer L. Berkowitz, Michael J. Betti, Alfredo Brusco, Ashley Cannon, Giulia Caron, Yanmin Chen, Molly M. Crenshaw, Laurence Cuisset, Cynthia J. Curry, Hossein Darvish, Serwet Demirdas, Maria Descartes, Jessica Douglas, David A. Dyment, Houda Zghal Elloumi, Giuseppe Ermondi, Marie Faoucher, Emily G. Farrow, Stephanie A. Felker, Heather Fisher, Anna C. E. Hurst, Pascal Joset, Stanislav Kmoch, Benjamin R. Leadem, Marina Macchiaiolo, Martin Magner, Giorgia Mandrile, Francesca Mattioli, Megan McEown, Sarah K. Meadows, Livija Medne, Naomi J. L. Meeks, Sarah Montgomery, Melanie P. Napier, Marvin Natowicz, Kimberly M. Newberry, Marcello Niceta, Lenka Noskova, Catherine Nowak, Amanda G. Noyes, Matthew Osmond, Verdiana Pullano, Chloé Quélin, Simin Rahimi-Aliabadi, Anita Rauch, Sylvia Redon, Alexandre Reymond, Caitlin R. Schwager, Elizabeth A. Sellars, Angela Scheuerle, Elena Shukarova-Angelovska, Cara Skraban, Bonnie R. Sullivan, Marco Tartaglia, Isabelle Thiffault, Kevin Uguen, Luis A. Umaña, Yolande van Bever, Saskia N. van der Crabben, Marjon A. van Slegtenhorst, Quinten Waisfisz, Richard M. Myers, Gregory M. Cooper

الوصف: Neurodevelopmental disorders (NDDs) often result from highly penetrant variation in one of many genes, including genes not yet characterized. Using the MatchMaker Exchange, we assembled a cohort of 22 individuals with rare, protein-altering variation in the X-linked transcriptional coregulator gene ZMYM3. Most (n=19) individuals were males; 15 males had maternally-inherited alleles, three of the variants in males arose de novo, and one had unknown inheritance. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n=21) are missense, two of which are recurrent. Three unrelated males were identified with inherited variation at R441, a site at which variation has been previously reported in NDD-affected males, and two individuals have de novo variation at R1294. All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is highly expressed in the brain, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, ZMYM3R1274W, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including the presence of recurrent variation, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects, strongly supports ZMYM3 as a novel NDD gene.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::68bc5998075e24b5d233adf3505f0a1eTest
https://doi.org/10.1101/2022.09.29.22279724Test

المؤلفون: Reshmi Ramakrishnan, Catherine Quindipan, Claudia A. L. Ruivenkamp, Nicholas M. Allen, Mashaya Zaman, Daniela Q.C.M. Barge-Schaapveld, Annalisa Vetro, Stephanie Efthymiou, James R. Lupski, Kara C. Klemp, Zou Pan, Adam Jackson, Marielle E. van Gijn, Joshua Scheck, Marielle Alders, Mariet W. Elting, Karla A. Peña-Guerra, Stephen R. Braddock, Rolph Pfundt, Ivan K. Chinn, Lin Yang, Lauren Schenck, Xiaodong Wang, Melissa Lees, Houda Zghal Elloumi, Shehla Mohammed, Sally Ann Lynch, Henry Houlden, Jennifer Keller-Ramey, Stefan T. Arold, Anneke Kievit, Jefferey McGlothlin, Marjon van Slegtenhorst, Marjolein H. Willemsen, Hannah K. Robinson, Bert B.A. de Vries, Irma Järvelä, Kelly J. Cardona-Londoño, Yolande van Bever, Abeltje M. Polstra, Neda Mazaheri, Barbara W. van Paassen, Maura R.Z. Ruzhnikov, Lewis Pang, Theresa Mihalic Mosher, J. Lawrence Merritt, Jing Peng, Sadegheh Haghshenas, Amy Crunk, Christian Gilissen, Fleur Vansenne, Cacha M.P.C.D. Peeters-Scholte, Richard E. Person, Hamid Galehdari, Leena Lauronen, Abbey M. Putnam, Jennifer Kerkhof, Matthew Pastore, Angela Sun, Caroline M. Kehoe, Alexandra Garza-Flores, Julia Baptista, Martino Montomoli, Selina H. Banu, Tahsin Stefan Barakat, Adi Reich, Luis Alberto Pedroza, Laurence E. Walsh, Renzo Guerrini, Ghayda M. Mirzaa, Peter D. Turnpenny, J. Austin Hamm, Xi Lin, Kristina Lanko, Reza Maroofian, Tuomo Määttä, Yana Lara-Taranchenko, Kim L. McBride, Jenny Thies, Andrew E. Timms, Shaoping Huang, Suzanne M. Leal, Daniel C. Koboldt, Rebecca Baud, Gretchen E. Rosso, Haley McConkey, Matthew A. Deardorff, Marjolein J.A. Weerts, Francisco J. Guzmán-Vega, Tamison Jewett, Siddharth Banka, Kristin G. Monaghan, Isabelle Schrauwen, Bekim Sadikovic, Sanjay M. Sisodiya, Victoria Harrison, Susanne Koning

مصطلحات موضوعية: Genetics, 0303 health sciences, Language delay, Mechanism (biology), Biology, medicine.disease, Penetrance, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, medicine, Autism, Global developmental delay, Epigenetics, 030217 neurology & neurosurgery, 030304 developmental biology

الوصف: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::16c8e215afe52e022ad5ae98a3578594Test
https://doi.org/10.1101/2021.02.11.430742Test