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1. Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

Author

Megan Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei, Kathryn Elliott, Dana H. Goodloe, S. Joy Dean, Catherine Gooch, Brianna K. Murray, Erin Swartz, Samantha A. Schrier Vergano, Meghan C. Towne, Kimberly Nugent, Elizabeth R. Roeder, Christina Kresge, Beth A. Pletcher, Katheryn Grand, John M. Graham Jr., Ryan Gates, Natalia Gomez‐Ospina, Subhadra Ramanathan, Robin Dawn Clark, Kimberly Glaser, Paul J. Benke, Julie S. Cohen, Ali Fatemi, Weiyi Mu, Kristin W. Baranano, Jill A. Madden, Cynthia S. Gubbels, Timothy W. Yu, Pankaj B. Agrawal, Mary‐Kathryn Chambers, Chanika Phornphutkul, John A. Pugh, Kate A. Tauber, Svetlana Azova, Jessica R. Smith, Anne O’Donnell‐Luria, Hannah Medsker, Siddharth Srivastava, Deborah Krakow, Daniela N. Schweitzer, and Valerie A. Arboleda

Subjects
CRISPR, Genitopatellar syndrome, KAT6B‐related disorders, phenotypic spectrum, Say‐Barber‐Biesecker‐Young‐Simpson syndrome, variable expressivity, rare genetic diagnosis, Genetics, QH426-470
Abstract

Abstract The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say‐Barber‐Biesecker‐Young‐Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B‐related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B‐related disorders.

Published
2021
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4. SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability

Author

Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus LeBlanc, Emma van Reempts, Frederic Tran Mau-Them, Ingrid M. Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J. Louie, Michael J. Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley McConkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R. Roeder, Tadahiro Mitani, Jennifer E. Posey, Daniel Calame, Hagith Yonath, Jill A. Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R. Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello, Bogaert, Elke, Garde, Aurore, Gautier, Thierry, Rooney, Kathleen, Duffourd, Yanni, Leblanc, Pontu, van Reempts, Emma, Tran Mau-Them, Frederic, Wentzensen, Ingrid M, Au, Kit Sing, Richardson, Kate, Northrup, Hope, Gatinois, Vincent, Geneviève, David, Louie, Raymond J, Lyons, Michael J, Laulund, Lone Walentin, Brasch-Andersen, Charlotte, Maxel Juul, Trine, El It, Fatima, Marle, Nathalie, Callier, Patrick, Relator, Raissa, Haghshenas, Sadegheh, Mcconkey, Haley, Kerkhof, Jennifer, Cesario, Claudia, Novelli, Antonio, Brunetti-Pierri, Nicola, Pinelli, Michele, Pennamen, Perrine, Naudion, Sophie, Legendre, Marine, Courdier, Cécile, Trimouille, Aurelien, Fenzy, Martine Doco, Pais, Lynn, Yeung, Alison, Nugent, Kimberly, Roeder, Elizabeth R, Mitani, Tadahiro, Posey, Jennifer E, Calame, Daniel, Yonath, Hagith, Rosenfeld, Jill A, Musante, Luciana, Faletra, Flavio, Montanari, Francesca, Sartor, Giovanna, Vancini, Alessandra, Seri, Marco, Besmond, Claude, Poirier, Karine, Hubert, Laurence, Hemelsoet, Dimitri, Munnich, Arnold, Lupski, James R, Philippe, Christophe, Thauvin-Robinet, Christel, Faivre, Laurence, Sadikovic, Bekim, Govin, Jérôme, Dermaut, Bart, and Vitobello, Antonio

Subjects
SRSF1, splicing, epigenetic signature, Medicine and Health Sciences, Genetics, Drosophila, neurodevelopmental disorder, Genetics (clinical), haploinsufficiency
Abstract

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.

Published
2023

5. PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Author

Anna Lehman, Christina T. Rüsch, Angela F. Brady, Julie S. Cohen, Millan S. Patel, Rani Sachdev, Usha Kini, Elizabeth E. Palmer, Reza Maroofian, Sonal Mahida, Karen Stals, Roger L. Ladda, Yoshiko Murakami, Camille Tremblay-Laganière, Tahsin Stefan Barakat, Scott D. McLean, Fizza Akbar, Marilena Christoforou, Farah Ashrafzadeh, Melissa A. Walker, Grazia M.S. Mancini, Salman Kirmani, Kimberly Nugent, Philippe M. Campeau, Fatima Y. Ismail, Amanda Nagy, Sian Ellard, Stephanie Efthymiou, Bushra Afroze, Rebecca Macintosh, Saskia B. Wortmann, Danilo Bernardo, Rebecca Truty, Matias Wagner, Shahnaz Ibrahim, Tipu Sultan, Kristin W. Barañano, Stylianos E. Antonarakis, Yuta Maki, Thi Tuyet Mai Nguyen, Henry Houlden, Robert Steinfeld, Saadet Mercimek-Andrews, Taroh Kinoshita, Georg M. Stettner, Andrew C. Edmondson, Naila Ismayilova, Meisam Babaei, Heather M. McLaughlin, Mohammad Doosti, Ehsan Ghayoor Karimiani, and Clinical Genetics

Subjects
Autism Spectrum Disorder, Immunoglobulin D, Article, Cell membrane, chemistry.chemical_compound, Biosynthesis, Seizures, Intellectual Disability, medicine, Humans, Transferase, Gene, Genetics (clinical), Genetics, chemistry.chemical_classification, Virulence, biology, Membrane Proteins, Hypotonia, In vitro, Pedigree, Phosphotransferases (Alcohol Group Acceptor), Enzyme, medicine.anatomical_structure, chemistry, biology.protein, medicine.symptom
Abstract

Purpose Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. Methods We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. Results Phenotypic analysis of reported individuals reveals shared PIGG deficiency–associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. Conclusion This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions. Unlabelled Image

Published
2021
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6. Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders

Author

Sylvia A. Huisman, Fanny Mochel, Christel Depienne, Roberto Canitano, Sara S. Cathey, Kimberly Nugent, Konrad Platzer, Katherine L. Helbig, Deepali N. Shinde, Diego Lopergolo, Sandra Yang, Francesca Mari, Astrid S. Plomp, Berten Ceulemans, Sarah Weckhuysen, Agnès Rastetter, Nadja Ehmke, Julien Thevenon, Rami Abou Jamra, Elisa Benetti, Daniela del Gaudio, Elizabeth Roeder, Darrel Waggoner, Raymond J. Louie, Shawn Kacker, Manuel Holtgrewe, Alessandra Renieri, Susanne B. Kamphausen, Denise Horn, Ange Line Bruel, Carine Dalle, Quinten Waisfisz, Frank J. Kaiser, Golder N. Wilson, Human genetics, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Human Genetics, and Paediatric Genetics

Subjects
Male, 0301 basic medicine, Patch-Clamp Techniques, Movement disorders, Small-Conductance Calcium-Activated Potassium Channels, Medizin, Haploinsufficiency, 0302 clinical medicine, Missense mutation, Exome, Child, Frameshift Mutation, Exome sequencing, Genetics, Movement Disorders, Learning Disabilities, Middle Aged, Magnetic Resonance Imaging, White Matter, developmental delay, Child, Preschool, medicine.symptom, SK2 channel, KCNN2, ataxia, tremor, Adolescent, Adult, Cerebellar Ataxia, Electrophysiological Phenomena, Genetic Variation, Humans, Intellectual Disability, Mutation, Missense, Neurodevelopmental Disorders, Young Adult, Ataxia, Biology, Frameshift mutation, 03 medical and health sciences, medicine, Preschool, Cerebellar ataxia, 030104 developmental biology, Mutation, Neurology (clinical), Missense, 030217 neurology & neurosurgery
Abstract

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.

Published
2020
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7. Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

Author

Kathryn Elliott, Siddharth Srivastava, Meghan C. Towne, Hannah Medsker, Catherine Gooch, Robin D. Clark, John M. Graham, Chanika Phornphutkul, Jill A. Madden, Pankaj B. Agrawal, Maria F. Palafox, Deborah Krakow, Meghna Singh, Daniela N. Schweitzer, Ryan Gates, Ali Fatemi, Kimberly Nugent, Katheryn Grand, Samantha A. Schrier Vergano, Brianna K. Murray, Kate A. Tauber, Weiyi Mu, Erin Swartz, Timothy W. Yu, Julie S. Cohen, Kimberly Glaser, Svetlana Azova, Paul J. Benke, Mary Kathryn Chambers, Dana H. Goodloe, Christina Kresge, Valerie A. Arboleda, John A. Pugh, Kristin W. Barañano, Megan Yabumoto, S. Joy Dean, Beth A. Pletcher, Subhadra Ramanathan, Angela Wei, Jessica Kianmahd, Elizabeth Roeder, Natalia Gomez-Ospina, Jessica Smith, Cynthia S. Gubbels, and Anne H. O’Donnell-Luria

Subjects
Male, Say-Barber-Biesecker-Young-Simpson syndrome, rare genetic diagnosis, QH426-470, Bioinformatics, Kidney, Cohort Studies, Craniofacial Abnormalities, Congenital, Intellectual disability, Medicine, CRISPR, 2.1 Biological and endogenous factors, variable expressivity, rare genetic diagnosis, Medical diagnosis, Aetiology, Genetics (clinical), Heart Defects, Histone Acetyltransferases, Pediatric, Patella, Phenotype, Scrotum, Original Article, Abnormalities, KAT6B-related disorders, Multiple, Heart Defects, Congenital, Joint Instability, Genitopatellar syndrome, Genotype, Genetic counseling, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Genetic Counseling, Blepharophimosis, Medicinal and Biomolecular Chemistry, Rare Diseases, Clinical Research, variable expressivity, Intellectual Disability, Congenital Hypothyroidism, Genetics, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Genetic Testing, Craniofacial, Molecular Biology, Alleles, Genetic Association Studies, KAT6B‐related disorders, business.industry, Facies, Original Articles, medicine.disease, Say‐Barber‐Biesecker‐Young‐Simpson syndrome, Transcriptome Sequencing, Brain Disorders, Genetic Loci, Urogenital Abnormalities, Mutation, Congenital Structural Anomalies, Psychomotor Disorders, business, phenotypic spectrum
Abstract

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say‐Barber‐Biesecker‐Young‐Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B‐related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B‐related disorders., We describe 20 new cases harboring the KAT6B spectrum of disorders, which range from Say‐Barber‐Biesecker‐Young‐Simpson (SBBYSS) to Genitopatellar (GPS) syndrome or an intermediate phenotype. In our holistic approach, we expand the genotypic and phenotypic spectrum of KAT6B spectrum of disorders. Furthermore, we provide extensive clinical phenotyping, explore the impact of genetic counseling for these complex syndromes, and examine molecular mechanisms in RNA‐seq data in an in vitro cell model of truncating KAT6B mutations.

Published
2021

8. Recurrent Arginine Substitutions in the ACTG2 Gene are the Primary Driver of Disease Burden and Severity in Visceral Myopathy

Author

James D. Weisfeld-Adams, Sandra Heck, Margaret Harr, Jennifer E. Posey, James R. Lupski, Yazmin Enchautegui Colon, Bertrand Isidor, Pengfei Liu, Maciej Bagłaj, Austin Larson, Katherine B. Bosanko, Bert Callewaert, Nurit Assia Batzir, Maria Linda Rocha, Ashley Cannon, Michael F. Wangler, Leon Bofferding, Kimberly Nugent, Katerina Wells, Michael B. Petersen, Robert Smigiel, Skander Bouassida, Elizabeth Roeder, Arthur L. Beaudet, Helen Mar Fan, Pilar L. Magoulas, Ian Tully, Ronit Marom, Marjan M. Nezarati, Scott D. McLean, Shalini N. Jhangiani, Pranjali K Bhagwat, Anna C.E. Hurst, Adolfo D. Garnica, Zeynep Coban Akdemir, and Rebecca O. Littlejohn

Subjects
Adult, Male, medicine.medical_specialty, Arginine, Genotype, Colon, DNA Mutational Analysis, Urinary Bladder, Disease, Biology, Gastroenterology, Article, dysmotility, smooth muscle, 03 medical and health sciences, Young Adult, Internal medicine, visceral myopathy, Exome Sequencing, Genetics, medicine, Missense mutation, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Allele, Genetics (clinical), Exome sequencing, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, megacystis-microcolon intestinal hypoperistalsis, 030305 genetics & heredity, Intestinal Pseudo-Obstruction, Megacystis, Microcolon, medicine.disease, Actins, Transplantation, Phenotype, Amino Acid Substitution, Molecular Diagnostic Techniques, ACTG2, Mutation, Female
Abstract

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype–phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

Published
2020
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9. The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis

Author

Marie Falkenberg Smeland, Alina Kurolap, Michael J. Gambello, Ariel F. Martinez, Livija Medne, Melita Irving, Elizabeth Roeder, Holly Dubbs, Robert M. Petrovich, Elaine H. Zackai, Motoki Takaku, Kimberly Nugent, Bruce D. Gelb, Peter D. Turnpenny, Michael Parker, Maximilian Muenke, Thomas Smol, Arie van Haeringen, Hanne Hove, Hitoshi Kurumizaka, Sandra Whalen, Boris Keren, Philippe M. Campeau, Samantha A. Schrier Vergano, Lior Cohen, Pauline Terhal, Amy Kenney, Paul A. Wade, Jill Clayton-Smith, Jamal Ghoumid, Shane C. Quinonez, John Roberts, Katherine Lachlan, Mahim Jain, Estelle Colin, Melissa Rumple, Solveig Heide, Kay Metcalfe, Alban Ziegler, Hayley P. Lazar, Elizabeth T. DeChene, Cara M. Skraban, Michael Wright, Karin Weiss, Danielle Monteil, Tamar Paperna, Avni Santani, Hagit Baris Feldman, Bryan L. Krock, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Clinical Genetics, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Kennedy Krieger Institute [Baltimore], Department of Pediatrics, The University of Texas at San Antonio (UTSA), Universiteit Leiden [Leiden], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Children’s Hospital of Philadelphia (CHOP ), Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, University of Manchester [Manchester], Central Manchester University Hospitals NHS Foundation Trust, Waseda University, CHU Sainte Justine [Montréal], Cancer Genetics Branch, National Institute of Health (NIH)-National Human Genome Research Institute (NHGRI), and Southampton General Hospital

Subjects
0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Developmental Disabilities, 030105 genetics & heredity, chromatin remodeling, 12p13, Neurodevelopmental disorder, Intellectual disability, Missense mutation, Global developmental delay, Child, Genetics (clinical), Genetics, Syndrome, Phenotype, 3. Good health, intellectual disability, Child, Preschool, Female, medicine.symptom, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Adult, Heart Defects, Congenital, missense, Adolescent, Genotype, Mutation, Missense, Biology, Chromatin remodeling, Article, 12p13.31, 03 medical and health sciences, medicine, Humans, ATPase, Abnormalities, Multiple, Hearing Loss, Genetic Association Studies, Macrocephaly, Infant, Newborn, Infant, medicine.disease, Chromatin Assembly and Disassembly, Human genetics, Megalencephaly, Musculoskeletal Abnormalities, 030104 developmental biology, Neurodevelopmental Disorders, Transcription Factors
Abstract

Sifrim–Hitz–Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants in CHD4. In this study, we investigated the clinical spectrum of the disorder, genotype–phenotype correlations, and the effect of different missense variants on CHD4 function. We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype–phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.

Published
2020
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10. Further delineation of the phenotypic spectrum associated with hemizygous loss-of-function variants in NONO

Author

Marc C. Patterson, Thomas Courtin, Scott D. McLean, Jeanne Amiel, Kimberly Nugent, Daryl A. Scott, Maham Sewani, Sandra Whalen, Boris Keren, Yaping Yang, Patrick R. Blackburn, Jessica M. Tarnowski, Jill A. Rosenfeld, Pavel N. Pichurin, and Andres Hernandez-Garcia

Subjects
0301 basic medicine, Adult, Heart Defects, Congenital, Male, Developmental Disabilities, Gestational Age, 030105 genetics & heredity, Biology, Corpus callosum, 03 medical and health sciences, Frontal Bossing, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetics (clinical), Loss function, Hemizygote, Macrocephaly, RNA-Binding Proteins, Syndrome, medicine.disease, Hypotonia, DNA-Binding Proteins, 030104 developmental biology, Palpebral fissure, Phenotype, Child, Preschool, Mutation, Left ventricular noncompaction, Female, medicine.symptom
Abstract

The non-POU domain containing, octamer-binding gene, NONO, is located on chromosome Xq13.1 and encodes a member of a small family of RNA and DNA binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Hemizygous loss-of-function variants in NONO have been shown to cause mental retardation, X-linked, syndromic 34 in males. Features of this disorder can include a range of neurodevelopmental phenotypes, left ventricular noncompaction (LVNC), congenital heart defects, and CNS anomalies. To date only eight cases have been described in the literature. Here we report two unrelated patients and a miscarried fetus with loss-of-function variants in NONO. Their phenotypes, and a review of previously reported cases, demonstrate that hemizygous loss-of-function variants in NONO cause a recognizable genetic syndrome. The cardinal features of this condition include developmental delay, intellectual disability, hypotonia, macrocephaly, structural abnormalities affecting the corpus callosum and/or cerebellum, LVNC, congenital heart defects, and gastrointestinal/feeding issues. This syndrome also carries an increased risk for strabismus and cryptorchidism and is associated with dysmorphic features that include an elongated face, up/down-slanted palpebral fissures, frontal bossing, and malar hypoplasia.

Published
2019

11. Defining and expanding the phenotype of

Author

Katrine M, Johannesen, Diana, Mitter, Robert, Janowski, Christian, Roth, Joseph, Toulouse, Anne-Lise, Poulat, Dorothee M, Ville, Nicolas, Chatron, Eva, Brilstra, Karin, Geleijns, Alfred Peter, Born, Scott, McLean, Kimberly, Nugent, Gareth, Baynam, Cathryn, Poulton, Lauren, Dreyer, Dylan, Gration, Solveig, Schulz, Andrea, Dieckmann, Katherine L, Helbig, Andreas, Merkenschlager, Rami, Jamra, Anja, Finck, Elena, Gardella, Helle, Hjalgrim, Ghayda, Mirzaa, Francesco, Brancati, Tatjana, Bierhals, Jonas, Denecke, Maja, Hempel, Johannes R, Lemke, Guido, Rubboli, Petra, Muschke, Renzo, Guerrini, Annalisa, Vetro, Dierk, Niessing, Gaetan, Lesca, and Rikke S, Møller

Subjects
Article
Abstract

Objective The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy. Methods Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding. Results Biallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype. Conclusions These data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

Published
2019

12. De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Author

Yaping Yang, Sarah H. Elsea, Orly Elpeleg, Donna M. Muzny, Vinod Varghese, Hanoch Cassuto, Mohnish Suri, Sue Holder, AK Lampe, Weimin Bi, Wenmiao Zhu, Muriel Holder-Espinasse, Shane McKee, Christine M. Eng, Lihadh Al-Gazali, Vardiella Meiner, Aisha Al Shamsi, Kim L. McBride, Melissa Lees, June Anne Gold, Janet S. Soul, Soo Mi Park, Birgitta Bernhard, Sonal Mahida, Klaas J. Wierenga, Daryl A. Scott, Elizabeth Roeder, Kimberly Nugent, Vivienne McConnell, Jill M. Harris, Ed Blair, J. Lloyd Holder, Makanko Komara, Seema R. Lalani, Brett H. Graham, Andrea M. Lewis, Jill A. Rosenfeld, Ziva Ben-Neriah, Elizabeth A. Fanning, Richard A. Gibbs, Pengfei Liu, Lionel Van Maldergem, Fan Xia, Ludmila Matyakhina, James B. Gibson, Victoria Harrison, Julie Vogt, Francesco Vetrini, Rebecca O. Littlejohn, James R. Lupski, Ajith Kumar, Jennifer E. Posey, Margaret Marlatt, Joseph T. Alaimo, Matthew Pastore, Laurie H. Seaver, and Lindsay C. Burrage

Subjects
Male, 0301 basic medicine, lcsh:QH426-470, Adolescent, Developmental Disabilities, lcsh:Medicine, Haploinsufficiency, Craniofacial Abnormalities, Young Adult, 03 medical and health sciences, 0302 clinical medicine, INDEL Mutation, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Deletions, Child, Molecular Biology, Typographical error, Genetics (clinical), TCF20, Loss-of-function variants, Research, lcsh:R, Neurodevelopmental disorders, Infant, Smith–Magenis syndrome, medicine.disease, Research Highlight, 22q13, Hypotonia, 3. Good health, lcsh:Genetics, 030104 developmental biology, Child, Preschool, 030220 oncology & carcinogenesis, Muscle Hypotonia, Molecular Medicine, Female, Smith-Magenis Syndrome, medicine.symptom, Psychology, Transcription Factors, Clinical psychology
Abstract

Background Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith–Magenis syndrome (deletion/haploinsufficiency) and Potocki–Lupski syndrome (duplication/triplosensitivity). Methods Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith–Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective. Electronic supplementary material The online version of this article (10.1186/s13073-019-0623-0) contains supplementary material, which is available to authorized users.

Published
2019
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13. Germline findings based on patient phenotype of the Texas KidsCanSeq cohort: an interim analysis

Author

Shashikant Kulkarni, Sharon E. Plon, Emily Berenson, Christine M. Eng, Rachel Wyatt, Jessica Corredor, Jacquelyn Reuther, D. Williams Parsons, Lauren Desrosiers, Juan Carlos Bernini, Gail E. Tomlinson, Angshumoy Roy, Kimberly Nugent, Rebecca Althaus, Amy L. McGuire, Timothy C. Griffin, Rebecca O. Littlejohn, Jonathan Gill, George Miles, Kelly Vallance, and Sarah Scollon

Subjects
Oncology, medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Interim analysis, Biochemistry, Phenotype, Germline, Endocrinology, Internal medicine, Cohort, Genetics, Medicine, business, Molecular Biology
Published
2021
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14. Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy

Author

Gareth Baynam, Christian Roth, Joseph Toulouse, Guido Rubboli, Karin Geleijns, Jonas Denecke, Robert Janowski, Dylan Gration, Diana Mitter, Alfred Peter Born, Dierk Niessing, Anne-Lise Poulat, Kimberly Nugent, Cathryn Poulton, Renzo Guerrini, Ghayda M. Mirzaa, Nicolas Chatron, Scott D. McLean, Eva H. Brilstra, H. Hjalgrim, Annalisa Vetro, Dorothée Ville, Rami Abou Jamra, Lauren Dreyer, Francesco Brancati, Katrine M Johannesen, Petra Muschke, Maja Hempel, Rikke S. Møller, Katherine L. Helbig, Gaetan Lesca, Anja Finck, Andrea Dieckmann, Tatjana Bierhals, E. Gardella, Andreas Merkenschlager, Solveig Schulz, and Johannes R. Lemke

Subjects
0303 health sciences, Pediatrics, medicine.medical_specialty, Progressive microcephaly, Microcephaly, business.industry, Genetic counseling, Encephalopathy, medicine.disease, Irritability, Short stature, Hypotonia, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Genetics (clinical), 030304 developmental biology
Abstract

ObjectiveThe study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy.MethodsThrough diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.ResultsBiallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.ConclusionsThese data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

Published
2019
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15. Correction: The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

Author

Karin Weiss, Hayley P. Lazar, Alina Kurolap, Ariel F. Martinez, Tamar Paperna, Lior Cohen, Marie F. Smeland, Sandra Whalen, Solveig Heide, Boris Keren, Pauline Terhal, Melita Irving, Motoki Takaku, John D. Roberts, Robert M. Petrovich, Samantha A. Schrier Vergano, Amy Kenney, Hanne Hove, Elizabeth DeChene, Shane C. Quinonez, Estelle Colin, Alban Ziegler, Melissa Rumple, Mahim Jain, Danielle Monteil, Elizabeth R. Roeder, Kimberly Nugent, Arie van Haeringen, Michael Gambello, Avni Santani, Līvija Medne, Bryan Krock, Cara M. Skraban, Elaine H. Zackai, Holly A. Dubbs, Thomas Smol, Jamal Ghoumid, Michael J. Parker, Michael Wright, Peter Turnpenny, Jill Clayton-Smith, Kay Metcalfe, Hitoshi Kurumizaka, Bruce D. Gelb, Hagit Baris Feldman, Philippe M. Campeau, Maximilian Muenke, Paul A. Wade, and Katherine Lachlan

Subjects
Genetics (clinical)
Published
2020
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16. Correction to: De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Author

Kim L. McBride, Soo Mi Park, Richard A. Gibbs, Shane McKee, Melissa Lees, Wenmiao Zhu, Yaping Yang, Jill A. Rosenfeld, Vardiella Meiner, Elizabeth A. Fanning, Victoria Harrison, Lihadh Al-Gazali, Anne K. Lampe, Ed Blair, Sue Holder, Klaas J. Wierenga, Ajith Kuttannair Kumar, Fan Xia, Sarah H. Elsea, Andrea M. Lewis, Vivienne McConnell, Birgitta Bernhard, Orly Elpeleg, Mohnish Suri, Elizabeth Roeder, Lionel Van Maldergem, J. Lloyd Holder, Muriel Holder-Espinasse, Rebecca O. Littlejohn, Sonal Mahida, Aisha Al Shamsi, June Anne Gold, Joseph T. Alaimo, Ziva Ben-Neriah, Jennifer E. Posey, Vinod Varghese, Julie Vogt, Donna M. Muzny, Makanko Komara, Christine M. Eng, Daryl A. Scott, Francesco Vetrini, Brett H. Graham, Seema R. Lalani, Kimberly Nugent, Hanoch Cassuto, Weimin Bi, Jill M. Harris, Pengfei Liu, Matthew Pastore, Ludmila Matyakhina, James B. Gibson, James R. Lupski, Margaret Marlatt, Laurie H. Seaver, Lindsay C. Burrage, and Janet S. Soul

Subjects
Genetics, 0303 health sciences, lcsh:QH426-470, business.industry, lcsh:R, Correction, lcsh:Medicine, Smith–Magenis syndrome, medicine.disease, Genome, Hypotonia, 3. Good health, 03 medical and health sciences, lcsh:Genetics, 0302 clinical medicine, 030220 oncology & carcinogenesis, Intellectual disability, medicine, Molecular Medicine, medicine.symptom, business, Molecular Biology, Genetics (clinical), 030304 developmental biology
Abstract

It was highlighted that the original article [1] contained a typographical error in the Results section. Subject 17 was incorrectly cited as Subject 1. This Correction article shows the revised statement. The original article has been updated.

Published
2019
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17. Identification of novel candidate disease genes from de novo exonic copy number variants

Author

Christian P. Schaaf, Janice L. Smith, Rachel Westman, Ronit Marom, Laurence Faivre, Pawel Stankiewicz, Patricia I. Bader, Myla Ashfaq, Hsiao-Tuan Chao, Monica Proud, Hope Northrup, Lindsay E. Elton, Seema R. Lalani, Yaping Yang, Chester W. Brown, Kimberly Nugent, Lauren Dengle, James R. Lupski, Sandesh C.S. Nagamani, Heather G. Petrie, Bo Yuan, Robert Wildin, Carlos A. Bacino, Chad A. Shaw, Tomasz Gambin, Hannele Koillinen, La Donna Immken, Edward P. Buchanan, Zeynep Coban-Akdemir, Ankita Patel, Lisa Emrick, Diane Treadwell-Deering, Anita E. Beck, Nora Urraca, Sau Wai Cheung, Elizabeth Roeder, Amy M. Breman, Mathilde Lefebvre, Arthur L. Beaudet, Amber N. Pursley, Gary Bellus, Sung Hae L. Kang, Sailaja Golla, Jill A. Rosenfeld, Reuben Matalon, Michael P. Cummings, Pengfei Liu, Roya Mostafavi, Saunder Bernes, Shaun Varghese, Magdalena Walkiewicz, Weimin Bi, Department of Medical and Clinical Genetics, Medicum, and Clinicum

Subjects
0301 basic medicine, INTELLECTUAL DISABILITY, lcsh:Medicine, Serine-Threonine Kinase 3, Cohort Studies, CHROMOSOMAL MICROARRAY, Copy-number variation, de novo variants, Genetics (clinical), Genetics, education.field_of_study, Intracellular Signaling Peptides and Proteins, 1184 Genetics, developmental biology, physiology, Exons, 3. Good health, Exon targeted array CGH, Molecular Medicine, Intragenic copy number variants, DNA microarray, lcsh:QH426-470, DNA Copy Number Variations, Population, ARRAY CGH, Protein Serine-Threonine Kinases, Biology, COGNITIVE PHENOTYPES, GENOMIC DISORDERS, 03 medical and health sciences, MENDELIAN DISORDERS, Humans, CLINICAL DIAGNOSTIC-TEST, education, Molecular Biology, Gene, PERSISTENT GASTROESOPHAGEAL-REFLUX, Retrospective Studies, Homeodomain Proteins, CNVs, Whole genome sequencing, Autosome, Whole Genome Sequencing, Genome, Human, Research, AUTISM SPECTRUM DISORDER, SYNDROMIC DEVELOPMENTAL DELAY, lcsh:R, Genetic Diseases, Inborn, Membrane Proteins, Human genetics, lcsh:Genetics, 030104 developmental biology, Neurodevelopmental Disorders, Human genome, 3111 Biomedicine, Transcription Factors
Abstract

Background Exon-targeted microarrays can detect small (

Published
2017
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18. De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Author

Jill A. Rosenfeld, Dominique Bonneau, Deborah Barbouth, Stephen Sanders, Kimberly Nugent, Kimberly Glaser, Ignacio Briceño, Kyle Retterer, Sylvain Simon, Weimin Bi, Yaping Yang, Holly A.F. Stessman, Kristin G. Monaghan, Pawel Stankiewicz, Caroline Rooryck, Sébastien Küry, James R. Lupski, Xenia Latypova, Carlos A. Bacino, Stephanie Sacharow, Sandra Mercier, Evan E. Eichler, Marie Vincent, Elizabeth Roeder, Sébastien Schmitt, Thomas Besnard, Alberto Gómez, Ankita Patel, Brigitte Gilbert-Dussardier, Valérie Malan, Mathilde Nizon, Jessica Douglas, Annick Toutain, Peter-Michael Kloetzel, Anne-Sophie Denommé-Pichon, Frédéric Ebstein, Fan Xia, Laurent Pasquier, Megan T. Cho, Mathilde Pacault, Laurence Perrin-Sabourin, James B. Gibson, Bertrand Isidor, William J. Craigen, Bo Yuan, Stéphane Bézieau, Chad A. Shaw, Richard Redon, Janice L. Smith, Benjamin Cogné, Eric Bieth, Wallid Deb, Kamal Khan, Sylvie Odent, Andrea Lehmann, Tahir N. Khan, Philippe Parent, Christelle Golzio, Nicholas Katsanis, Marie-Line Jacquemont, Tomasz Gambin, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Boston Children's Hospital, Department of Medicine, Karolinska Institutet [Stockholm], Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Department of Pediatrics, The University of Texas at San Antonio (UTSA), LabEX IGO Immunothérapie Grand Ouest, Service de Cancéro-Dermatologie, Centre hospitalier universitaire de Nantes (CHU Nantes), Anti-tumor immunosurveillances and immunotherapy (CRCINA - Département INCIT - Equipe 3), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, CHU Pontchaillou [Rennes], Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Instituto de Genetica Humana, Pontificia Universidad Javeriana, Universitad de la Sabana, Baylor College of Medicine (BCM), Baylor University, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Human Disease Modeling, Duke University [Durham], National Heart, Lung, and Blood Institute, Wellcome Trust, French Ministry of Health, HUGODIMS, 2013, RC14_0107, Health Regional Agency from Poitou-Charentes, U54HG006542, US National Human Genome Research Institute, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Duke University Medical Center, Warsaw University of Technology [Warsaw], University of California [San Francisco] (UC San Francisco), University of California (UC), University of Miami, Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Robert Debré, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Nantes Université (Nantes Univ), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Biologie Neurovasculaire Intégrée [Angers] (CNRS UMR6214 - INSERM U771), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), 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 ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pontificia Universidad Javeriana (PUJ), University of Washington [Seattle], Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Jonchère, Laurent, Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), The University of Texas at San Antonio ( UTSA ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Anti-tumor immunosurveillances and immunotherapy ( CRCINA - Département INCIT - Equipe 3 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université d'Angers ( UA ) -CHU Angers, Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Centre de Référence Anomalies du Développement Ouest, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Hôpital Bretonneau-CHRU Tours, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Universidad de la Sabana, Baylor College of Medicine ( BCM ), Baylor College of Medicine, unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Duke university [Durham]

Subjects
Male, 0301 basic medicine, Microcephaly, Intellectual disability, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, 0302 clinical medicine, Neurodevelopmental disorder, Ubiquitin, PSMD12, Syndromic neurodevelopmental disorder, Child, Zebrafish, Genetics (clinical), Genetics, Proteasome 26S, Phenotype, proteasome 26S, intellectual disability, Child, Preschool, Female, Proteasome Endopeptidase Complex, Adolescent, DNA Copy Number Variations, syndromic neurodevelopmental disorder, Protein subunit, Down-Regulation, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Report, RPN5, ubiquitin, medicine, Animals, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Point mutation, Infant, Correction, biology.organism_classification, medicine.disease, Human genetics, Disease Models, Animal, 030104 developmental biology, Proteasome, Neurodevelopmental Disorders, biology.protein, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

12 páginas Trichosporon asahii es un hongo patógeno emergente reportado en la literatura médica principalmente en pacientes inmunocomprometidos. No obstante, el presente caso es inusual debido a que se trata de un paciente adulto joven inmunocompetente que presentó fungemia por T. asahii y al mismo tiempo desarrolló insuficiencia respiratoria aguda por bronquiolitis respiratoria y neumonía descamativa, la cual resolvió posterior al tratamiento antimicótico instaurado, soporte ventilatorio y vigilancia en Unidad de Cuidado Intesivo (UCI). Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

Published
2017
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