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1. Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

Author

Webb, Bryn D, Evans, Anthony, Naidich, Thomas P, Bird, Lynne M, Parikh, Sumit, Garcia, Meilin Fernandez, Henderson, Lindsay B, Millan, Francisca, Si, Yue, Brennand, Kristen J, Hung, Peter, Rucker, Janet C, Wheeler, Patricia G, and Schadt, Eric E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Brain Disorders, Rare Diseases, Neurosciences, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, Neurological, Adult, Ataxia, Child, Child, Preschool, Female, Haploinsufficiency, Humans, Magnetic Resonance Imaging, Male, Muscle Hypotonia, Mutation, Missense, Retrospective Studies, Syndrome, Transcription Factor Brn-3A, Tremor, United States, Exome Sequencing, Young Adult, ataxia, intention tremor, paroxysmal tonic upgaze, POU4F1, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome.

Published
2021

2. Rare de novo gain-of-function missense variants in DOT1L are associated with developmental delay and congenital anomalies

Author

Nil, Zelha, Deshwar, Ashish R., Huang, Yan, Barish, Scott, Zhang, Xi, Choufani, Sanaa, Le Quesne Stabej, Polona, Hayes, Ian, Yap, Patrick, Haldeman-Englert, Chad, Wilson, Carolyn, Prescott, Trine, Tveten, Kristian, Vøllo, Arve, Haynes, Devon, Wheeler, Patricia G., Zon, Jessica, Cytrynbaum, Cheryl, Jobling, Rebekah, Blyth, Moira, Banka, Siddharth, Afenjar, Alexandra, Mignot, Cyril, Robin-Renaldo, Florence, Keren, Boris, Kanca, Oguz, Mao, Xiao, Wegner, Daniel J., Sisco, Kathleen, Shinawi, Marwan, Wangler, Michael F., Weksberg, Rosanna, Yamamoto, Shinya, Costain, Gregory, and Bellen, Hugo J.

Published
2023
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3. Dominant variants in PRR12 result in unilateral or bilateral complex microphthalmia

Author

Reis, Linda M, Costakos, Deborah, Wheeler, Patricia G, Bardakjian, Tanya, Schneider, Adele, Fung, Simon SM, Genomics, University of Washington Center for Mendelian, and Semina, Elena V

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Ophthalmology and Optometry, Rare Diseases, Clinical Research, Eye Disease and Disorders of Vision, Neurosciences, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, 2.1 Biological and endogenous factors, Eye, Adolescent, Adult, Alleles, Anterior Eye Segment, Child, Child, Preschool, Corneal Opacity, Eye Abnormalities, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Membrane Proteins, Microphthalmos, Mutation, Pedigree, Phenotype, developmental ocular disorder, exome, microphthalmia, Peters anomaly, PRR12, unilateral, University of Washington Center for Mendelian Genomics, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Complex microphthalmia is characterized by small eyes with additional abnormalities that may include anterior segment dysgenesis. While many genes are known, a genetic cause is identified in only 4-30% of microphthalmia, with the lowest rate in unilateral cases. We identified four novel pathogenic loss-of-function alleles in PRR12 in families affected by complex microphthalmia and/or Peters anomaly, including two de novo, the first dominantly transmitted allele, as well as the first splicing variant. The ocular phenotypes were isolated with no additional systemic features observed in two unrelated families. Remarkably, ocular phenotypes were asymmetric in all individuals and unilateral (with structurally normal contralateral eye) in three. There are only three previously reported PRR12 variants identified in probands with intellectual disability, neuropsychiatric disorders, and iris anomalies. While some overlap with previously reported cases is seen, nonsyndromic developmental ocular anomalies are a novel phenotype for this gene. Additional phenotypic expansions included short stature and normal development/cognition, each noted in two individuals in this cohort, as well as absence of neuropsychiatric disorders in all. This study identifies new associations for PRR12 disruption in humans and presents a genetic diagnosis resulting in unilateral ocular phenotypes in a significant proportion of cases.

Published
2021

4. De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism

Author

Sacoto, Maria J Guillen, Tchasovnikarova, Iva A, Torti, Erin, Forster, Cara, Andrew, E Hallie, Anselm, Irina, Baranano, Kristin W, Briere, Lauren C, Cohen, Julie S, Craigen, William J, Cytrynbaum, Cheryl, Ekhilevitch, Nina, Elrick, Matthew J, Fatemi, Ali, Fraser, Jamie L, Gallagher, Renata C, Guerin, Andrea, Haynes, Devon, High, Frances A, Inglese, Cara N, Kiss, Courtney, Koenig, Mary Kay, Krier, Joel, Lindstrom, Kristin, Marble, Michael, Meddaugh, Hannah, Moran, Ellen S, Morel, Chantal F, Mu, Weiyi, Muller, Eric A, Nance, Jessica, Natowicz, Marvin R, Numis, Adam L, Ostrem, Bridget, Pappas, John, Stafstrom, Carl E, Streff, Haley, Sweetser, David A, Szybowska, Marta, Network, Undiagnosed Diseases, Walker, Melissa A, Wang, Wei, Weiss, Karin, Weksberg, Rosanna, Wheeler, Patricia G, Yoon, Grace, Kingston, Robert E, and Juusola, Jane

Subjects
Neurodegenerative, Rare Diseases, Pediatric, Genetics, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Neurosciences, Congenital Structural Anomalies, Clinical Research, Dental/Oral and Craniofacial Disease, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adenosine Triphosphatases, Adolescent, Adult, Child, Child, Preschool, Craniofacial Abnormalities, Female, Genetic Diseases, Inborn, Growth Disorders, Heterozygote, Humans, Infant, Intellectual Disability, Male, Microcephaly, Middle Aged, Mutation, Neurodevelopmental Disorders, Phenotype, Transcription Factors, Young Adult, Undiagnosed Diseases Network, CMT2Z, Leigh-like disease, MORC2, developmental delay, intellectual disability, microcephaly, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.

Published
2020

5. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author

Coursimault, Juliette, Guerrot, Anne-Marie, Morrow, Michelle M., Schramm, Catherine, Zamora, Francisca Millan, Shanmugham, Anita, Liu, Shuxi, Zou, Fanggeng, Bilan, Frédéric, Le Guyader, Gwenaël, Bruel, Ange-Line, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Tran Mau-Them, Frédéric, Tessarech, Marine, Colin, Estelle, El Chehadeh, Salima, Gérard, Bénédicte, Schaefer, Elise, Cogne, Benjamin, Isidor, Bertrand, Nizon, Mathilde, Doummar, Diane, Valence, Stéphanie, Héron, Delphine, Keren, Boris, Mignot, Cyril, Coutton, Charles, Devillard, Françoise, Alaix, Anne-Sophie, Amiel, Jeanne, Colleaux, Laurence, Munnich, Arnold, Poirier, Karine, Rio, Marlène, Rondeau, Sophie, Barcia, Giulia, Callewaert, Bert, Dheedene, Annelies, Kumps, Candy, Vergult, Sarah, Menten, Björn, Chung, Wendy K., Hernan, Rebecca, Larson, Austin, Nori, Kelly, Stewart, Sarah, Wheless, James, Kresge, Christina, Pletcher, Beth A., Caumes, Roseline, Smol, Thomas, Sigaudy, Sabine, Coubes, Christine, Helm, Margaret, Smith, Rosemarie, Morrison, Jennifer, Wheeler, Patricia G., Kritzer, Amy, Jouret, Guillaume, Afenjar, Alexandra, Deleuze, Jean-François, Olaso, Robert, Boland, Anne, Poitou, Christine, Frebourg, Thierry, Houdayer, Claude, Saugier-Veber, Pascale, Nicolas, Gaël, and Lecoquierre, François

Published
2022
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6. WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features

Author

Skraban, Cara M, Wells, Constance F, Markose, Preetha, Cho, Megan T, Nesbitt, Addie I, Au, PY Billie, Begtrup, Amber, Bernat, John A, Bird, Lynne M, Cao, Kajia, de Brouwer, Arjan PM, Denenberg, Elizabeth H, Douglas, Ganka, Gibson, Kristin M, Grand, Katheryn, Goldenberg, Alice, Innes, A Micheil, Juusola, Jane, Kempers, Marlies, Kinning, Esther, Markie, David M, Owens, Martina M, Payne, Katelyn, Person, Richard, Pfundt, Rolph, Stocco, Amber, Turner, Claire LS, Verbeek, Nienke E, Walsh, Laurence E, Warner, Taylor C, Wheeler, Patricia G, Wieczorek, Dagmar, Wilkens, Alisha B, Zonneveld-Huijssoon, Evelien, Study, Deciphering Developmental Disorders, Kleefstra, Tjitske, Robertson, Stephen P, Santani, Avni, van Gassen, Koen LI, and Deardorff, Matthew A

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Dental/Oral and Craniofacial Disease, Rare Diseases, Neurodegenerative, Epilepsy, Clinical Research, Pediatric, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Base Sequence, Child, Preschool, Chromosome Deletion, Facies, Female, Gait, Growth and Development, Haploinsufficiency, Humans, Intellectual Disability, Male, Mutation, Proteins, RNA Stability, Seizures, Syndrome, Deciphering Developmental Disorders Study, WD-40, WDR protein, WDR26, intellectual disability, seizure, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.

Published
2017

7. Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

Author

Zanoni, Paolo, Steindl, Katharina, Sengupta, Deepanwita, Joset, Pascal, Bahr, Angela, Sticht, Heinrich, Lang-Muritano, Mariarosaria, van Ravenswaaij-Arts, Conny M. A., Shinawi, Marwan, Andrews, Marisa, Attie-Bitach, Tania, Maystadt, Isabelle, Belnap, Newell, Benoit, Valerie, Delplancq, Geoffroy, de Vries, Bert B. A., Grotto, Sarah, Lacombe, Didier, Larson, Austin, Mourmans, Jeroen, Õunap, Katrin, Petrilli, Giulia, Pfundt, Rolph, Ramsey, Keri, Blok, Lot Snijders, Tsatsaris, Vassilis, Vitobello, Antonio, Faivre, Laurence, Wheeler, Patricia G., Wevers, Marijke R., Wojcik, Monica, Zweier, Markus, Gozani, Or, and Rauch, Anita

Published
2021
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8. Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Author

Chowdhury, Fuad, Wang, Lei, Al-Raqad, Mohammed, Amor, David J., Baxová, Alice, Bendová, Šárka, Biamino, Elisa, Brusco, Alfredo, Caluseriu, Oana, Cox, Nancy J., Froukh, Tawfiq, Gunay-Aygun, Meral, Hančárová, Miroslava, Haynes, Devon, Heide, Solveig, Hoganson, George, Kaname, Tadashi, Keren, Boris, Kosaki, Kenjiro, Kubota, Kazuo, Lemons, Jennifer M., Magriña, Maria A., Mark, Paul R., McDonald, Marie T., Montgomery, Sarah, Morley, Gina M., Ohnishi, Hidenori, Okamoto, Nobuhiko, Rodriguez-Buritica, David, Rump, Patrick, Sedláček, Zdeněk, Schatz, Krista, Streff, Haley, Uehara, Tomoko, Walia, Jagdeep S., Wheeler, Patricia G., Wiesener, Antje, Zweier, Christiane, Kawakami, Koichi, Wentzensen, Ingrid M., Lalani, Seema R., Siu, Victoria M., Bi, Weimin, and Balci, Tugce B.

Published
2021
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9. Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY‐associated diseases.

Author

Cavestro, Chiara, Morra, Francesca, Legati, Andrea, D'Amato, Marco, Nasca, Alessia, Iuso, Arcangela, Lubarr, Naomi, Morrison, Jennifer L., Wheeler, Patricia G., Serra‐Juhé, Clara, Rodríguez‐Santiago, Benjamín, Turón‐Viñas, Eulalia, Prouteau, Clement, Barth, Magalie, Hayflick, Susan J., Ghezzi, Daniele, Tiranti, Valeria, and Di Meo, Ivano

Subjects
PHENOTYPES, EPILEPSY, CELL communication, COENZYME A, AUTISM spectrum disorders, TRANSCRIPTOMES
Abstract

Objective: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein‐associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY‐related disorders. Methods: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. Results: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY‐related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4′‐phosphopantetheinylated proteins were significantly reduced in COASY patients. Interpretation: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY‐associated diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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10. DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract

Author

Blackburn, Alexandria T. M., Bekheirnia, Nasim, Uma, Vanessa C., Corkins, Mark E., Xu, Yuxiao, Rosenfeld, Jill A., Bainbridge, Matthew N., Yang, Yaping, Liu, Pengfei, Madan-Khetarpal, Suneeta, Delgado, Mauricio R., Hudgins, Louanne, Krantz, Ian, Rodriguez-Buritica, David, Wheeler, Patricia G., Al-Gazali, Lihadh, Mohamed Saeed Mohamed Al Shamsi, Aisha, Gomez-Ospina, Natalia, Chao, Hsiao-Tuan, Mirzaa, Ghayda M., Scheuerle, Angela E., Kukolich, Mary K., Scaglia, Fernando, Eng, Christine, Willsey, Helen Rankin, Braun, Michael C., Lamb, Dolores J., Miller, Rachel K., and Bekheirnia, Mir Reza

Published
2019
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11. PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

Author

Ebstein, Frédéric, primary, Küry, Sébastien, additional, Most, Victoria, additional, Rosenfelt, Cory, additional, Scott-Boyer, Marie-Pier, additional, van Woerden, Geeske M., additional, Besnard, Thomas, additional, Papendorf, Jonas Johannes, additional, Studencka-Turski, Maja, additional, Wang, Tianyun, additional, Hsieh, Tzung-Chien, additional, Golnik, Richard, additional, Baldridge, Dustin, additional, Forster, Cara, additional, de Konink, Charlotte, additional, Teurlings, Selina M.W., additional, Vignard, Virginie, additional, van Jaarsveld, Richard H., additional, Ades, Lesley, additional, Cogné, Benjamin, additional, Mignot, Cyril, additional, Deb, Wallid, additional, Jongmans, Marjolijn C.J., additional, Cole, F. Sessions, additional, van den Boogaard, Marie-José H., additional, Wambach, Jennifer A., additional, Wegner, Daniel J., additional, Yang, Sandra, additional, Hannig, Vickie, additional, Brault, Jennifer Ann, additional, Zadeh, Neda, additional, Bennetts, Bruce, additional, Keren, Boris, additional, Gélineau, Anne-Claire, additional, Powis, Zöe, additional, Towne, Meghan, additional, Bachman, Kristine, additional, Seeley, Andrea, additional, Beck, Anita E., additional, Morrison, Jennifer, additional, Westman, Rachel, additional, Averill, Kelly, additional, Brunet, Theresa, additional, Haasters, Judith, additional, Carter, Melissa T., additional, Osmond, Matthew, additional, Wheeler, Patricia G., additional, Forzano, Francesca, additional, Mohammed, Shehla, additional, Trakadis, Yannis, additional, Accogli, Andrea, additional, Harrison, Rachel, additional, Guo, Yiran, additional, Hakonarson, Hakon, additional, Rondeau, Sophie, additional, Baujat, Geneviève, additional, Barcia, Giulia, additional, Feichtinger, René Günther, additional, Mayr, Johannes Adalbert, additional, Preisel, Martin, additional, Laumonnier, Frédéric, additional, Kallinich, Tilmann, additional, Knaus, Alexej, additional, Isidor, Bertrand, additional, Krawitz, Peter, additional, Völker, Uwe, additional, Hammer, Elke, additional, Droit, Arnaud, additional, Eichler, Evan E., additional, Elgersma, Ype, additional, Hildebrand, Peter W., additional, Bolduc, François, additional, Krüger, Elke, additional, and Bézieau, Stéphane, additional

Published
2023
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12. Novel biallelic variants expand the phenotype of NAA20 ‐related syndrome

Author

D'Onofrio, Gianluca, primary, Cuccurullo, Claudia, additional, Larsen, Silje Kathrine, additional, Severino, Mariasavina, additional, D'Amico, Alessandra, additional, Brønstad, Kirsten, additional, AlOwain, Mohammed, additional, Morrison, Jennifer L., additional, Wheeler, Patricia G., additional, Webb, Bryn D., additional, Alfalah, Abdullah, additional, Iacomino, Michele, additional, Uva, Paolo, additional, Coppola, Antonietta, additional, Merla, Giuseppe, additional, Salpietro, Vincenzo Damiano, additional, Zara, Federico, additional, Striano, Pasquale, additional, Accogli, Andrea, additional, Arnesen, Thomas, additional, and Bilo, Leonilda, additional

Published
2023
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13. PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

Author

Genetica Sectie Genoomdiagnostiek, Genetica Klinische Genetica, Cancer, Child Health, Ebstein, Frédéric, Küry, Sébastien, Most, Victoria, Rosenfelt, Cory, Scott-Boyer, Marie-Pier, van Woerden, Geeske M, Besnard, Thomas, Papendorf, Jonas Johannes, Studencka-Turski, Maja, Wang, Tianyun, Hsieh, Tzung-Chien, Golnik, Richard, Baldridge, Dustin, Forster, Cara, de Konink, Charlotte, Teurlings, Selina M W, Vignard, Virginie, van Jaarsveld, Richard H, Ades, Lesley, Cogné, Benjamin, Mignot, Cyril, Deb, Wallid, Jongmans, Marjolijn C J, Cole, F Sessions, van den Boogaard, Marie-José H, Wambach, Jennifer A, Wegner, Daniel J, Yang, Sandra, Hannig, Vickie, Brault, Jennifer Ann, Zadeh, Neda, Bennetts, Bruce, Keren, Boris, Gélineau, Anne-Claire, Powis, Zöe, Towne, Meghan, Bachman, Kristine, Seeley, Andrea, Beck, Anita E, Morrison, Jennifer, Westman, Rachel, Averill, Kelly, Brunet, Theresa, Haasters, Judith, Carter, Melissa T, Osmond, Matthew, Wheeler, Patricia G, Forzano, Francesca, Mohammed, Shehla, Trakadis, Yannis, Accogli, Andrea, Harrison, Rachel, Guo, Yiran, Hakonarson, Hakon, Rondeau, Sophie, Baujat, Geneviève, Barcia, Giulia, Feichtinger, René Günther, Mayr, Johannes Adalbert, Preisel, Martin, Laumonnier, Frédéric, Kallinich, Tilmann, Knaus, Alexej, Isidor, Bertrand, Krawitz, Peter, Völker, Uwe, Hammer, Elke, Droit, Arnaud, Eichler, Evan E, Elgersma, Ype, Hildebrand, Peter W, Bolduc, François, Krüger, Elke, Bézieau, Stéphane, Genetica Sectie Genoomdiagnostiek, Genetica Klinische Genetica, Cancer, Child Health, Ebstein, Frédéric, Küry, Sébastien, Most, Victoria, Rosenfelt, Cory, Scott-Boyer, Marie-Pier, van Woerden, Geeske M, Besnard, Thomas, Papendorf, Jonas Johannes, Studencka-Turski, Maja, Wang, Tianyun, Hsieh, Tzung-Chien, Golnik, Richard, Baldridge, Dustin, Forster, Cara, de Konink, Charlotte, Teurlings, Selina M W, Vignard, Virginie, van Jaarsveld, Richard H, Ades, Lesley, Cogné, Benjamin, Mignot, Cyril, Deb, Wallid, Jongmans, Marjolijn C J, Cole, F Sessions, van den Boogaard, Marie-José H, Wambach, Jennifer A, Wegner, Daniel J, Yang, Sandra, Hannig, Vickie, Brault, Jennifer Ann, Zadeh, Neda, Bennetts, Bruce, Keren, Boris, Gélineau, Anne-Claire, Powis, Zöe, Towne, Meghan, Bachman, Kristine, Seeley, Andrea, Beck, Anita E, Morrison, Jennifer, Westman, Rachel, Averill, Kelly, Brunet, Theresa, Haasters, Judith, Carter, Melissa T, Osmond, Matthew, Wheeler, Patricia G, Forzano, Francesca, Mohammed, Shehla, Trakadis, Yannis, Accogli, Andrea, Harrison, Rachel, Guo, Yiran, Hakonarson, Hakon, Rondeau, Sophie, Baujat, Geneviève, Barcia, Giulia, Feichtinger, René Günther, Mayr, Johannes Adalbert, Preisel, Martin, Laumonnier, Frédéric, Kallinich, Tilmann, Knaus, Alexej, Isidor, Bertrand, Krawitz, Peter, Völker, Uwe, Hammer, Elke, Droit, Arnaud, Eichler, Evan E, Elgersma, Ype, Hildebrand, Peter W, Bolduc, François, Krüger, Elke, and Bézieau, Stéphane

Published
2023

14. Correction: DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract

Author

Blackburn, Alexandria T. M., Bekheirnia, Nasim, Uma, Vanessa C., Corkins, Mark E., Xu, Yuxiao, Rosenfeld, Jill A., Bainbridge, Matthew N., Yang, Yaping, Liu, Pengfei, Madan-Khetarpal, Suneeta, Delgado, Mauricio R., Hudgins, Louanne, Krantz, Ian, Rodriguez-Buritica, David, Wheeler, Patricia G., Al-Gazali, Lihadh, Shamsi, Aisha Mohamed Saeed Mohamed Al, Gomez-Ospina, Natalia, Chao, Hsiao-Tuan, Mirzaa, Ghayda M., Scheuerle, Angela E., Kukolich, Mary K., Scaglia, Fernando, Eng, Christine, Willsey, Helen Rankin, Braun, Michael C., Lamb, Dolores J., Miller, Rachel K., and Bekheirnia, Mir Reza

Published
2020
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16. Characterization of a possible founder synonymous variant in TECTA in multiple individuals with autosomal recessive hearing loss

Author

Chen, Robert, primary, Diaz‐Miranda, Maria Alejandra, additional, Aref‐Eshghi, Erfan, additional, Hartman, Tiffiney R., additional, Griffith, Christopher, additional, Morrison, Jennifer L., additional, Wheeler, Patricia G., additional, Torti, Erin, additional, Richard, Gabriele, additional, Kenna, Margaret, additional, Dechene, Elizabeth T., additional, Spinner, Nancy B., additional, Bai, Renkui, additional, Conlin, Laura K., additional, Krantz, Ian D., additional, Amr, Sami S., additional, and Luo, Minjie, additional

Published
2022
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17. De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Author

Genetica Klinische Genetica, Brain, Child Health, Galosi, Serena, Edani, Ban H, Martinelli, Simone, Hansikova, Hana, Eklund, Erik A, Caputi, Caterina, Masuelli, Laura, Corsten-Janssen, Nicole, Srour, Myriam, Oegema, Renske, Bosch, Daniëlle G M, Ellis, Colin A, Amlie-Wolf, Louise, Accogli, Andrea, Atallah, Isis, Averdunk, Luisa, Barañano, Kristin W, Bei, Roberto, Bagnasco, Irene, Brusco, Alfredo, Demarest, Scott, Alaix, Anne-Sophie, Di Bonaventura, Carlo, Distelmaier, Felix, Elmslie, Frances, Gan-Or, Ziv, Good, Jean-Marc, Gripp, Karen, Kamsteeg, Erik-Jan, Macnamara, Ellen, Marcelis, Carlo, Mercier, Noëlle, Peeden, Joseph, Pizzi, Simone, Pannone, Luca, Shinawi, Marwan, Toro, Camilo, Verbeek, Nienke E, Venkateswaran, Sunita, Wheeler, Patricia G, Zdrazilova, Lucie, Zhang, Rong, Zorzi, Giovanna, Guerrini, Renzo, Sessa, William C, Lefeber, Dirk, Tartaglia, Marco, Hamdan, Fadi F, Grabińska, Kariona A, Leuzzi, Vincenzo, Genetica Klinische Genetica, Brain, Child Health, Galosi, Serena, Edani, Ban H, Martinelli, Simone, Hansikova, Hana, Eklund, Erik A, Caputi, Caterina, Masuelli, Laura, Corsten-Janssen, Nicole, Srour, Myriam, Oegema, Renske, Bosch, Daniëlle G M, Ellis, Colin A, Amlie-Wolf, Louise, Accogli, Andrea, Atallah, Isis, Averdunk, Luisa, Barañano, Kristin W, Bei, Roberto, Bagnasco, Irene, Brusco, Alfredo, Demarest, Scott, Alaix, Anne-Sophie, Di Bonaventura, Carlo, Distelmaier, Felix, Elmslie, Frances, Gan-Or, Ziv, Good, Jean-Marc, Gripp, Karen, Kamsteeg, Erik-Jan, Macnamara, Ellen, Marcelis, Carlo, Mercier, Noëlle, Peeden, Joseph, Pizzi, Simone, Pannone, Luca, Shinawi, Marwan, Toro, Camilo, Verbeek, Nienke E, Venkateswaran, Sunita, Wheeler, Patricia G, Zdrazilova, Lucie, Zhang, Rong, Zorzi, Giovanna, Guerrini, Renzo, Sessa, William C, Lefeber, Dirk, Tartaglia, Marco, Hamdan, Fadi F, Grabińska, Kariona A, and Leuzzi, Vincenzo

Published
2022

19. MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects

Author

Coursimault, Juliette, primary, Guerrot, Anne-Marie, additional, Morrow, Michelle M., additional, Schramm, Catherine, additional, Zamora, Francisca Millan, additional, Shanmugham, Anita, additional, Liu, Shuxi, additional, Zou, Fanggeng, additional, Bilan, Frédéric, additional, Le Guyader, Gwenaël, additional, Bruel, Ange-Line, additional, Denommé-Pichon, Anne-Sophie, additional, Faivre, Laurence, additional, Tran Mau-Them, Frédéric, additional, Tessarech, Marine, additional, Colin, Estelle, additional, El Chehadeh, Salima, additional, Gérard, Bénédicte, additional, Schaefer, Elise, additional, Cogne, Benjamin, additional, Isidor, Bertrand, additional, Nizon, Mathilde, additional, Doummar, Diane, additional, Valence, Stéphanie, additional, Héron, Delphine, additional, Keren, Boris, additional, Mignot, Cyril, additional, Coutton, Charles, additional, Devillard, Françoise, additional, Alaix, Anne-Sophie, additional, Amiel, Jeanne, additional, Colleaux, Laurence, additional, Munnich, Arnold, additional, Poirier, Karine, additional, Rio, Marlène, additional, Rondeau, Sophie, additional, Barcia, Giulia, additional, Callewaert, Bert, additional, Dheedene, Annelies, additional, Kumps, Candy, additional, Vergult, Sarah, additional, Menten, Björn, additional, Chung, Wendy K., additional, Hernan, Rebecca, additional, Larson, Austin, additional, Nori, Kelly, additional, Stewart, Sarah, additional, Wheless, James, additional, Kresge, Christina, additional, Pletcher, Beth A., additional, Caumes, Roseline, additional, Smol, Thomas, additional, Sigaudy, Sabine, additional, Coubes, Christine, additional, Helm, Margaret, additional, Smith, Rosemarie, additional, Morrison, Jennifer, additional, Wheeler, Patricia G., additional, Kritzer, Amy, additional, Jouret, Guillaume, additional, Afenjar, Alexandra, additional, Deleuze, Jean-François, additional, Olaso, Robert, additional, Boland, Anne, additional, Poitou, Christine, additional, Frebourg, Thierry, additional, Houdayer, Claude, additional, Saugier-Veber, Pascale, additional, Nicolas, Gaël, additional, and Lecoquierre, François, additional

Published
2021
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20. Missense NAA20 variantsimpairing the NatB protein N-terminal acetyltransferase cause autosomal recessivedevelopmental delay, intellectual disability, and microcephaly

Author

Morrison, Jennifer, primary, Altuwaijri, Norah K., additional, Brønstad, Kirsten, additional, Aksnes, Henriette, additional, Alsaif, Hessa S., additional, Evans, Anthony, additional, Hashem, Mais, additional, Wheeler, Patricia G., additional, Webb, Bryn D., additional, Alkuraya, Fowzan S., additional, and Arnesen, Thomas, additional

Published
2021
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22. Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation.

Author

Shimada, Shino, Ng, Bobby G., White, Amy L., Nickander, Kim K., Turgeon, Coleman, Liedtke, Kristen L., Lam, Christina T., Font-Montgomery, Esperanza, Lourenco, Charles M., He, Miao, Peck, Dawn S., Umana, Luis A., Uhles, Crescenda L., Haynes, Devon, Wheeler, Patricia G., Bamshad, Michael J., Nickerson, Deborah A., Cushing, Tom, Gates, Ryan, and Gomez-Ospina, Natalia

Abstract

Purpose To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in MOGS. Methods Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG. Results Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal. Conclusion The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease. [ABSTRACT FROM AUTHOR]

Published
2022
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23. De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Author

Galosi, Serena, primary, Edani, Ban H, additional, Martinelli, Simone, additional, Hansikova, Hana, additional, Eklund, Erik A, additional, Caputi, Caterina, additional, Masuelli, Laura, additional, Corsten-Janssen, Nicole, additional, Srour, Myriam, additional, Oegema, Renske, additional, Bosch, Daniëlle G M, additional, Ellis, Colin A, additional, Amlie-Wolf, Louise, additional, Accogli, Andrea, additional, Atallah, Isis, additional, Averdunk, Luisa, additional, Barañano, Kristin W, additional, Bei, Roberto, additional, Bagnasco, Irene, additional, Brusco, Alfredo, additional, Demarest, Scott, additional, Alaix, Anne-Sophie, additional, Di Bonaventura, Carlo, additional, Distelmaier, Felix, additional, Elmslie, Frances, additional, Gan-Or, Ziv, additional, Good, Jean-Marc, additional, Gripp, Karen, additional, Kamsteeg, Erik-Jan, additional, Macnamara, Ellen, additional, Marcelis, Carlo, additional, Mercier, Noëlle, additional, Peeden, Joseph, additional, Pizzi, Simone, additional, Pannone, Luca, additional, Shinawi, Marwan, additional, Toro, Camilo, additional, Verbeek, Nienke E, additional, Venkateswaran, Sunita, additional, Wheeler, Patricia G, additional, Zdrazilova, Lucie, additional, Zhang, Rong, additional, Zorzi, Giovanna, additional, Guerrini, Renzo, additional, Sessa, William C, additional, Lefeber, Dirk J, additional, Tartaglia, Marco, additional, Hamdan, Fadi F, additional, Grabińska, Kariona A, additional, and Leuzzi, Vincenzo, additional

Published
2021
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24. Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in PTLS

Author

Feng Zhang, Potocki, Lorraine, Sampson, Jacinda B., Pengfei Liu, Sanchez-Valle, Amarilis, Robbins-Furman, Patricia, Navarro, Alicia Delicado, Wheeler, Patricia G., Spence, J. Edward, Brasington, Campbell K., Withers, Marjoire A., and Lupski, James R.

Subjects
Hybridization -- Research, Gene mutations -- Research, Genetic disorders -- Causes of, Genetic disorders -- Research, Biological sciences
Abstract

A study uses oligonucleotide-based comparative genomic hybridization and recombination hot spot analyses to identify uncommon recurrent Potocki-Lupski syndrome (PTLS)-associated duplications and the distribution of rearrangement types and mechanisms in PTLS. The results facilitate better insights into the role of de novo mutations and their underlying mechanisms which result in genomic rearrangements that cause genomic disorders.

Published
2010

25. Novel Mutations Widen the Phenotypic Spectrum of Slow Skeletal/β-Cardiac Myosin (MYH7) Distal Myopathy

Author

Lamont, Phillipa J., Wallefeld, William, Hilton-Jones, David, Udd, Bjarne, Argov, Zohar, Barboi, Alexandru C., Bonneman, Carsten, Boycott, Kym M., Bushby, Kate, Connolly, Anne M., Davies, Nicholas, Beggs, Alan H., Cox, Gerald F., Dastgir, Jahannaz, DeChene, Elizabeth T., Gooding, Rebecca, Jungbluth, Heinz, Muelas, Nuria, Palmio, Johanna, Penttilä, Sini, Schmedding, Eric, Suominen, Tiina, Straub, Volker, Staples, Christopher, Van den Bergh, Peter Y.K., Vilchez, Juan J., Wagner, Kathryn R., Wheeler, Patricia G., Wraige, Elizabeth, and Laing, Nigel G.

Published
2014
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27. De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism

Author

Guillen Sacoto, Maria J, Tchasovnikarova, Iva A, Torti, Erin, Forster, Cara, Andrew, E Hallie, Anselm, Irina, Baranano, Kristin W, Briere, Lauren C, Cohen, Julie S, Craigen, William J, Cytrynbaum, Cheryl, Ekhilevitch, Nina, Elrick, Matthew J, Fatemi, Ali, Fraser, Jamie L, Gallagher, Renata C, Guerin, Andrea, Haynes, Devon, High, Frances A, Inglese, Cara N, Kiss, Courtney, Koenig, Mary Kay, Krier, Joel, Lindstrom, Kristin, Marble, Michael, Meddaugh, Hannah, Moran, Ellen S, Morel, Chantal F, Mu, Weiyi, Muller, Eric A, Nance, Jessica, Natowicz, Marvin R, Numis, Adam L, Ostrem, Bridget, Pappas, John, Stafstrom, Carl E, Streff, Haley, Sweetser, David A, Szybowska, Marta, Undiagnosed Diseases Network, Walker, Melissa A, Wang, Wei, Weiss, Karin, Weksberg, Rosanna, Wheeler, Patricia G, Yoon, Grace, Kingston, Robert E, and Juusola, Jane

Subjects
Adult, Male, Heterozygote, Adolescent, Intellectual and Developmental Disabilities (IDD), MORC2, Neurodegenerative, Medical and Health Sciences, Craniofacial Abnormalities, Young Adult, Rare Diseases, Clinical Research, Intellectual Disability, Genetics, Humans, 2.1 Biological and endogenous factors, microcephaly, Dental/Oral and Craniofacial Disease, Aetiology, Child, Preschool, Growth Disorders, Adenosine Triphosphatases, Pediatric, Genetics & Heredity, Neurosciences, Infant, Undiagnosed Diseases Network, Middle Aged, CMT2Z, Biological Sciences, Brain Disorders, developmental delay, Inborn, Phenotype, Genetic Diseases, Neurodevelopmental Disorders, Mutation, Neurological, Congenital Structural Anomalies, Female, Leigh-like disease, Transcription Factors
Abstract

MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.

Published
2020

28. Recurrent HERV-H-Mediated 3q13.2–q13.31 Deletions Cause a Syndrome of Hypotonia and Motor, Language, and Cognitive Delays

Author

Shuvarikov, Andrey, Campbell, Ian M., Dittwald, Piotr, Neill, Nicholas J., Bialer, Martin G., Moore, Christine, Wheeler, Patricia G., Wallace, Stephanie E., Hannibal, Mark C., Murray, Michael F., Giovanni, Monica A., Terespolsky, Deborah, Sodhi, Sandi, Cassina, Matteo, Viskochil, David, Moghaddam, Billur, Herman, Kristin, Brown, Chester W., Beck, Christine R., Gambin, Anna, Cheung, Sau Wai, Patel, Ankita, Lamb, Allen N., Shaffer, Lisa G., Ellison, Jay W., Ravnan, Britt J., Stankiewicz, Paweł, and Rosenfeld, Jill A.

Published
2013
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29. De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism

Author

Guillen Sacoto, Maria J., primary, Tchasovnikarova, Iva A., additional, Torti, Erin, additional, Forster, Cara, additional, Andrew, E. Hallie, additional, Anselm, Irina, additional, Baranano, Kristin W., additional, Briere, Lauren C., additional, Cohen, Julie S., additional, Craigen, William J., additional, Cytrynbaum, Cheryl, additional, Ekhilevitch, Nina, additional, Elrick, Matthew J., additional, Fatemi, Ali, additional, Fraser, Jamie L., additional, Gallagher, Renata C., additional, Guerin, Andrea, additional, Haynes, Devon, additional, High, Frances A., additional, Inglese, Cara N., additional, Kiss, Courtney, additional, Koenig, Mary Kay, additional, Krier, Joel, additional, Lindstrom, Kristin, additional, Marble, Michael, additional, Meddaugh, Hannah, additional, Moran, Ellen S., additional, Morel, Chantal F., additional, Mu, Weiyi, additional, Muller, Eric A., additional, Nance, Jessica, additional, Natowicz, Marvin R., additional, Numis, Adam L., additional, Ostrem, Bridget, additional, Pappas, John, additional, Stafstrom, Carl E., additional, Streff, Haley, additional, Sweetser, David A., additional, Szybowska, Marta, additional, Walker, Melissa A., additional, Wang, Wei, additional, Weiss, Karin, additional, Weksberg, Rosanna, additional, Wheeler, Patricia G., additional, Yoon, Grace, additional, Kingston, Robert E., additional, and Juusola, Jane, additional

Published
2020
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35. A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies

Author

Gonçalves, Sara, Patat, Julie, Guida, Maria Clara, Lachaussée, Noelle, Arrondel, Christelle, Helmstädter, Martin, Boyer, Olivia, Gribouval, Olivier, Gubler, Marie-Claire, Mollet, Geraldine, Rio, Marlène, Charbit, Marina, Bole-Feysot, Christine, Nitschke, Patrick, Huber, Tobias B., Wheeler, Patricia G., Haynes, Devon, Juusola, Jane, Billette de Villemeur, Thierry, Nava, Caroline, Afenjar, Alexandra, Keren, Boris, Bodmer, Rolf, Antignac, Corinne, and Simons, Matias

Subjects
Arthropoda, lcsh:QH426-470, Cardiology, Research and Analysis Methods, Model Organisms, Mathematical and Statistical Techniques, Animal Cells, Medicine and Health Sciences, Congenital Disorders, Morphogenesis, Genetics, Animals, Birth Defects, Statistical Methods, Connective Tissue Cells, Analysis of Variance, Drosophila Melanogaster, Organisms, Biology and Life Sciences, Eukaryota, Heart, Kidneys, Animal Models, Cell Biology, Renal System, Fibroblasts, Invertebrates, Insects, lcsh:Genetics, Biological Tissue, Experimental Organism Systems, Connective Tissue, Mutation, Physical Sciences, Cardiovascular Anatomy, Microcephaly, Drosophila, Anatomy, Cellular Types, Arrhythmia, Mathematics, Statistics (Mathematics), Research Article, Developmental Biology
Abstract

Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders., Author summary Genetic diseases with complex syndromic constellations may be caused by mutations in more than one gene. Most examples studied so far describe genetic interactions of known disease genes, suggesting that a large number of multilocus diseases remain unexplored. Assessment of mutation pathogenicity can be achieved using animal models. One main advantage of using Drosophila is that it allows easy in vivo gene manipulation in cell types that are relevant for the disease. Here, we report the pathogenicity of ADD3 mutations in three families with intellectual disability, microcephaly, cataracts and skeletal defects. Moreover, we provide evidence that the renal and cardiac phenotypes in one of the families could be unmasked by a homozygous variant in the lysine acetyltransferase encoding KAT2B gene. In Drosophila, this variant resulted not only in decreased viability, but also in functional defects in cardiomyocytes and nephrocytes, the latter being similar to mammalian podocytes. Our study implicates KAT2B as a susceptibility gene for steroid-resistant nephrotic syndrome (SRNS) and cardiomyopathy and emphasizes the importance of protein acetylation in kidney and heart function.

Published
2018

36. Loss-of-function and missense variants in NSD2cause decreased methylation activity and are associated with a distinct developmental phenotype

Author

Zanoni, Paolo, Steindl, Katharina, Sengupta, Deepanwita, Joset, Pascal, Bahr, Angela, Sticht, Heinrich, Lang-Muritano, Mariarosaria, van Ravenswaaij-Arts, Conny M.A., Shinawi, Marwan, Andrews, Marisa, Attie-Bitach, Tania, Maystadt, Isabelle, Belnap, Newell, Benoit, Valerie, Delplancq, Geoffroy, de Vries, Bert B.A., Grotto, Sarah, Lacombe, Didier, Larson, Austin, Mourmans, Jeroen, Õunap, Katrin, Petrilli, Giulia, Pfundt, Rolph, Ramsey, Keri, Blok, Lot Snijders, Tsatsaris, Vassilis, Vitobello, Antonio, Faivre, Laurence, Wheeler, Patricia G., Wevers, Marijke R., Wojcik, Monica, Zweier, Markus, Gozani, Or, and Rauch, Anita

Abstract

Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2pathogenic variants remains poorly understood.

Published
2021
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37. Haploinsufficiency of PRR12causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Author

Chowdhury, Fuad, Wang, Lei, Al-Raqad, Mohammed, Amor, David J., Baxová, Alice, Bendová, Šárka, Biamino, Elisa, Brusco, Alfredo, Caluseriu, Oana, Cox, Nancy J., Froukh, Tawfiq, Gunay-Aygun, Meral, Hančárová, Miroslava, Haynes, Devon, Heide, Solveig, Hoganson, George, Kaname, Tadashi, Keren, Boris, Kosaki, Kenjiro, Kubota, Kazuo, Lemons, Jennifer M., Magriña, Maria A., Mark, Paul R., McDonald, Marie T., Montgomery, Sarah, Morley, Gina M., Ohnishi, Hidenori, Okamoto, Nobuhiko, Rodriguez-Buritica, David, Rump, Patrick, Sedláček, Zdeněk, Schatz, Krista, Streff, Haley, Uehara, Tomoko, Walia, Jagdeep S., Wheeler, Patricia G., Wiesener, Antje, Zweier, Christiane, Kawakami, Koichi, Wentzensen, Ingrid M., Lalani, Seema R., Siu, Victoria M., Bi, Weimin, and Balci, Tugce B.

Abstract

Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency.

Published
2021
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38. De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

Author

Hiatt, Susan M., primary, Neu, Matthew B., additional, Ramaker, Ryne C., additional, Hardigan, Andrew A., additional, Prokop, Jeremy W., additional, Hancarova, Miroslava, additional, Prchalova, Darina, additional, Havlovicova, Marketa, additional, Prchal, Jan, additional, Stranecky, Viktor, additional, Yim, Dwight K. C., additional, Powis, Zöe, additional, Keren, Boris, additional, Nava, Caroline, additional, Mignot, Cyril, additional, Rio, Marlene, additional, Revah-Politi, Anya, additional, Hemati, Parisa, additional, Stong, Nicholas, additional, Iglesias, Alejandro D., additional, Suchy, Sharon F., additional, Willaert, Rebecca, additional, Wentzensen, Ingrid M., additional, Wheeler, Patricia G., additional, Brick, Lauren, additional, Kozenko, Mariya, additional, Hurst, Anna C. E., additional, Wheless, James W., additional, Lacassie, Yves, additional, Myers, Richard M., additional, Barsh, Gregory S., additional, Sedlacek, Zdenek, additional, and Cooper, Gregory M., additional

Published
2018
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39. Correction: A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies

Author

Gonçalves, Sara, primary, Patat, Julie, additional, Guida, Maria Clara, additional, Lachaussée, Noelle, additional, Arrondel, Christelle, additional, Helmstädter, Martin, additional, Boyer, Olivia, additional, Gribouval, Olivier, additional, Gubler, Marie-Claire, additional, Mollet, Geraldine, additional, Rio, Marlène, additional, Charbit, Marina, additional, Bole-Feysot, Christine, additional, Nitschke, Patrick, additional, Huber, Tobias B., additional, Wheeler, Patricia G., additional, Haynes, Devon, additional, Juusola, Jane, additional, Villemeur, Thierry Billette de, additional, Nava, Caroline, additional, Afenjar, Alexandra, additional, Keren, Boris, additional, Bodmer, Rolf, additional, Antignac, Corinne, additional, and Simons, Matias, additional

Published
2018
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40. De novomutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

Author

Hiatt, Susan M., primary, Neu, Matthew B., additional, Ramaker, Ryne C., additional, Hardigan, Andrew A., additional, Prokop, Jeremy W., additional, Hancarova, Miroslava, additional, Prchalova, Darina, additional, Havlovicova, Marketa, additional, Prchal, Jan, additional, Stranecky, Viktor, additional, Yim, Dwight K.C., additional, Powis, Zöe, additional, Keren, Boris, additional, Nava, Caroline, additional, Mignot, Cyril, additional, Rio, Marlene, additional, Revah-Politi, Anya, additional, Hemati, Parisa, additional, Stong, Nicholas, additional, Iglesias, Alejandro D., additional, Suchy, Sharon F., additional, Willaert, Rebecca, additional, Wentzensen, Ingrid M., additional, Wheeler, Patricia G., additional, Brick, Lauren, additional, Kozenko, Mariya, additional, Hurst, Anna C.E., additional, Wheless, James W., additional, Lacassie, Yves, additional, Myers, Richard M., additional, Barsh, Gregory S., additional, Sedlacek, Zdenek, additional, and Cooper, Gregory M., additional

Published
2018
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41. Mutations That Alter the Carboxy‐Terminal‐Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype

Author

Cundy, Tim, primary, Dray, Michael, additional, Delahunt, John, additional, Hald, Jannie Dahl, additional, Langdahl, Bente, additional, Li, Chumei, additional, Szybowska, Marta, additional, Mohammed, Shehla, additional, Duncan, Emma L, additional, McInerney‐Leo, Aideen M, additional, Wheeler, Patricia G, additional, Roschger, Paul, additional, Klaushofer, Klaus, additional, Rai, Jyoti, additional, Weis, MaryAnn, additional, Eyre, David, additional, Schwarze, Ulrike, additional, and Byers, Peter H, additional

Published
2018
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42. WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features

Author

Genetica, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Skraban, Cara M, Wells, Constance F, Markose, Preetha, Cho, Megan T., Nesbitt, Addie I, Au, P Y Billie, Begtrup, Amber, Bernat, John A, Bird, Lynne M., Cao, Kajia, de Brouwer, Arjan P M, Denenberg, Elizabeth H, Douglas, Ganka, Gibson, Kristin M, Grand, Katheryn, Goldenberg, Alice, Innes, A. Micheil, Juusola, Jane, Kempers, Marlies, Kinning, Esther, Markie, David M, Owens, Martina M, Payne, Katelyn, Person, Richard, Pfundt, Rolph, Stocco, Amber, Turner, Claire L S, Verbeek, Nienke E., Walsh, Laurence E, Warner, Taylor C, Wheeler, Patricia G., Wieczorek, Dagmar, Wilkens, Alisha B, Zonneveld-Huijssoon, Evelien, Kleefstra, Tjitske, Robertson, Stephen P., Santani, Avni, van Gassen, Koen L.I., Deardorff, Matthew A, Genetica, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Skraban, Cara M, Wells, Constance F, Markose, Preetha, Cho, Megan T., Nesbitt, Addie I, Au, P Y Billie, Begtrup, Amber, Bernat, John A, Bird, Lynne M., Cao, Kajia, de Brouwer, Arjan P M, Denenberg, Elizabeth H, Douglas, Ganka, Gibson, Kristin M, Grand, Katheryn, Goldenberg, Alice, Innes, A. Micheil, Juusola, Jane, Kempers, Marlies, Kinning, Esther, Markie, David M, Owens, Martina M, Payne, Katelyn, Person, Richard, Pfundt, Rolph, Stocco, Amber, Turner, Claire L S, Verbeek, Nienke E., Walsh, Laurence E, Warner, Taylor C, Wheeler, Patricia G., Wieczorek, Dagmar, Wilkens, Alisha B, Zonneveld-Huijssoon, Evelien, Kleefstra, Tjitske, Robertson, Stephen P., Santani, Avni, van Gassen, Koen L.I., and Deardorff, Matthew A

Published
2017

44. Mutations in HIVEP2 are associated with developmental delay, intellectual disability, and dysmorphic features

Author

Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Steinfeld, Hallie, Cho, Megan T., Retterer, Kyle, Person, Rick, Schaefer, G. Bradley, Danylchuk, Noelle, Malik, Saleem, Wechsler, Stephanie Burns, Wheeler, Patricia G., van Gassen, Koen L I, Terhal, P. A., Verhoeven, Virginie J M, van Slegtenhorst, Marjon A., Monaghan, Kristin G., Henderson, Lindsay B., Chung, Wendy K., Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Steinfeld, Hallie, Cho, Megan T., Retterer, Kyle, Person, Rick, Schaefer, G. Bradley, Danylchuk, Noelle, Malik, Saleem, Wechsler, Stephanie Burns, Wheeler, Patricia G., van Gassen, Koen L I, Terhal, P. A., Verhoeven, Virginie J M, van Slegtenhorst, Marjon A., Monaghan, Kristin G., Henderson, Lindsay B., and Chung, Wendy K.

Published
2016

45. SRD5A3-CDG: Expanding the phenotype of a congenital disorder of glycosylation with emphasis on adult onset features

Author

Wheeler, Patricia G., primary, Ng, Bobby G., additional, Sanford, Laura, additional, Sutton, V. Reid, additional, Bartholomew, Dennis W., additional, Pastore, Matthew T., additional, Bamshad, Michael J., additional, Kircher, Martin, additional, Buckingham, Kati J., additional, Nickerson, Deborah A., additional, Shendure, Jay, additional, and Freeze, Hudson H., additional

Published
2016
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46. De novo POGZ mutations are associated with neurodevelopmental disorders and microcephaly

Author

Ye, Yizhou, primary, Cho, Megan T., additional, Retterer, Kyle, additional, Alexander, Nora, additional, Ben-Omran, Tawfeg, additional, Al-Mureikhi, Mariam, additional, Cristian, Ingrid, additional, Wheeler, Patricia G., additional, Crain, Carrie, additional, Zand, Dina, additional, Weinstein, Veronique, additional, Vernon, Hilary J., additional, McClellan, Rebecca, additional, Krishnamurthy, Vidya, additional, Vitazka, Patrik, additional, Millan, Francisca, additional, and Chung, Wendy K., additional

Published
2015
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47. De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay

Author

Yang, Hui, primary, Douglas, Ganka, additional, Monaghan, Kristin G., additional, Retterer, Kyle, additional, Cho, Megan T., additional, Escobar, Luis F., additional, Tucker, Megan E., additional, Stoler, Joan, additional, Rodan, Lance H., additional, Stein, Diane, additional, Marks, Warren, additional, Enns, Gregory M., additional, Platt, Julia, additional, Cox, Rachel, additional, Wheeler, Patricia G., additional, Crain, Carrie, additional, Calhoun, Amy, additional, Tryon, Rebecca, additional, Richard, Gabriele, additional, Vitazka, Patrik, additional, and Chung, Wendy K., additional

Published
2015
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48. Novel, Compound Heterozygous, Single-Nucleotide Variants inMARS2Associated with Developmental Delay, Poor Growth, and Sensorineural Hearing Loss

Author

Webb, Bryn D., primary, Wheeler, Patricia G., additional, Hagen, Jacob J., additional, Cohen, Ninette, additional, Linderman, Michael D., additional, Diaz, George A., additional, Naidich, Thomas P., additional, Rodenburg, Richard J., additional, Houten, Sander M., additional, and Schadt, Eric E., additional

Published
2015
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49. Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes-Brocks Syndrome.

Author

Webb, Bryn D., Metikala, Sanjeeva, Wheeler, Patricia G., Sherpa, Mingma D., Houten, Sander M., Horb, Marko E., and Schadt, Eric E.

Abstract

ABSTRACT A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 ( DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419* variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419* protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes-Brocks syndrome. [ABSTRACT FROM AUTHOR]

Published
2017
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