Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Genome Medicine

Candace Muss¹  Pengfei Liu²  Jill Rosenfeld³  Hilde Peeters⁴  Ghayda M. Mirzaa⁵  Kun Xia⁶  Heena Panjwani⁷  Micah Pepper⁷  Rachel K. Earl⁸  Raphael A. Bernier⁸  Marie Bournez⁹  Irene Valenzuela Palafoll^1,10  Florence Petit^1,11  Tomasz Nowakowski^1,12  Chang N. Kim^1,12  Bert Callewaert^1,13  Mathilde Lauridsen^1,14  Kristina Sorensen^1,14  Christina Fagerberg^1,14  Charlotte Brasch-Andersen^1,14  Robert Stratton^1,15  Orly Elpeleg^1,16  Boris Keren^1,17  Cyril Mignot^1,17  Marleen E. H. Simon^1,18  Koen L. I. van Gassen^1,18  Madelyn A. Gillentine^1,19  Tianyun Wang^1,19  Kendra Hoekzema^1,19  Hui Guo^2,20  Evan E. Eichler^2,21  Bert B. A. De Vries^2,22  Lisenka E. L. M. Vissers^2,22  Jessica Sebastian^2,23  Jodie Vento^2,23  Suneeta Madan-Khetarpal^2,24  Frank Kooy^2,25  Marije Meuwissen^2,25  Anna Lehman^2,26  Elena Lopez-Rangel^2,27  Kerry M. White^2,28  Carlos A. Bacino^2,29  Magnus Nordenskjold^3,30  Malin Kvarnung^3,30  Anna Lindstrand^3,30  Ann Nordgren^3,30  Siddharth Srivastava^3,31  Irina Anselm^3,31  Sabeen Syed^3,32  Agnese Scatigno^3,33  Anna Cereda^3,33  Celenie K. Christensen^3,34  Gifty Bhat^3,35  Katherine Cobian^3,35  Paul Levy^3,36  Lynne M. Bird^3,37  Meredith S. Wright^3,38  Jennifer Friedman^3,39  Timothy Lotze^4,40  Farida Abid^4,41  Edward J. Espineli^4,41  Bonnie Sullivan^4,42  Shuang Yan^4,42  Susan Hughes^4,43  Erin Torti^4,44  Silvia Maitz^4,45  Mary Kukolich^4,46  Lucia Ortega^4,46  Alice Basinger^4,46  Margaret Drummond-Borg^4,46  Meredith Philips^4,46  Timothy Feyma^4,47  Lars Kjærsgaard Hansen^4,48  Laurence Faivre^4,49  Sarah Schuhmann^5,50  Antje Wiesener^5,50  Christiane Zweier^5,50  Davor Lessel^5,51  Divya Vats^5,52  Maria Iascone^5,53  John Pappas^5,54  Shane Mckee^5,55  Corrado Romano^5,56  Maurizio Elia^5,56  Ornella Galesi^5,56  Kory Keller^5,57  Itai Berger^5,58  Kara Simpson^5,59  Jozef Gecz^6,60  Alexandra Afenjar^6,61  Sophie Mathieu^6,61  Paldeep Atwal^6,62  L. Manace Benman^6,63  Isabelle Thiffault^6,64  Antonio Vitobello^6,65  Ginevra Zanni^6,66  Enrico Bertini^6,66  Julien Thevenon^6,67 

[1] Al Dupont Hospital for Children, Wilmington, DE, USA;Baylor Genetics Laboratories, Houston, TX, USA;Baylor Genetics Laboratories, Houston, TX, USA;Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA;Center for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium;Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, USA;Department of Pediatrics, University of Washington, Seattle, WA, USA;Brotman Baty Institute for Precision Medicine, Seattle, WA, USA;Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China;Center on Human Development and Disability, University of Washington, Seattle, WA, USA;Seattle Children’s Autism Center, Seattle, WA, USA;Center on Human Development and Disability, University of Washington, Seattle, WA, USA;Seattle Children’s Autism Center, Seattle, WA, USA;Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA;Centre de Référence Maladies Rares « déficience intellectuelle », Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France;Centre de Référence Maladies Rares « Anomalies du Développement et Syndromes malformatifs »​ Université Bourgogne Franche-Comté, Dijon, France;Centre de référence Anomalies du développement, CHU Grenoble-Alpes, Grenoble, France;Clinique de Génétique, Hôpital Jeanne de Flandre, Bâtiment Modulaire, CHU, 59037, Lille Cedex, France;Department of Anatomy, University of California, San Francisco, CA, USA;Department of Psychiatry, University of California, San Francisco, CA, USA;Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, USA;The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA;Department of Biomolecular Medicine, Ghent University Hospital, Ghent, Belgium;Department of Clinical Genetics, Odense University Hospital, Odense, Denmark;Department of Genetics, Driscoll Children’s Hospital, Corpus Christi, TX, USA;Department of Genetics, Hadassah, Hebrew University Medical Center, Jerusalem, Israel;Department of Genetics, Hópital Pitié-Salpêtrière, Paris, France;Department of Genetics, University Medical Center, Utrecht University, Utrecht, The Netherlands;Department of Genome Sciences, University of Washington School of Medicine, 3720 15th Ave NE S413A, Box 355065, 981095-5065, Seattle, WA, USA;Department of Genome Sciences, University of Washington School of Medicine, 3720 15th Ave NE S413A, Box 355065, 981095-5065, Seattle, WA, USA;Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China;Department of Genome Sciences, University of Washington School of Medicine, 3720 15th Ave NE S413A, Box 355065, 981095-5065, Seattle, WA, USA;Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA;Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA;Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA;UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA;Department of Medical Genetics, University of Antwerp, Antwerp, Belgium;Department of Medical Genetics, University of British Columbia, Vancouver, Canada;BC Children’s Hospital and BC Women’s Hospital, Vancouver, BC, Canada;Department of Medical Genetics, University of British Columbia, Vancouver, Canada;Division of Developmental Pediatrics, Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada;Sunny Hill Health Centre for Children, Vancouver, BC, Canada;Department of Medical and Molecular Genetics, IU Health, Indianapolis, IN, USA;Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA;Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden;Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden;Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;Department of Pediatric Gastroenterology, Driscoll Children’s Hospital, Corpus Christi, TX, USA;Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA;Department of Pediatrics, Section of Genetics, University of Illinois at Chicago, Chicago, IL, USA;Department of Pediatrics, The Children’s Hospital at Montefiore, Bronx, NY, USA;Department of Pediatrics, University of California San Diego, San Diego, CA, USA;Genetics/Dysmorphology, Rady Children’s Hospital San Diego, San Diego, CA, USA;Department of Pediatrics, University of California San Diego, San Diego, CA, USA;Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA;Department of Pediatrics, University of California San Diego, San Diego, CA, USA;Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA;Department of Neurosciences, University of California San Diego, San Diego, CA, USA;Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA;Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA;Texas Children’s Hospital, Houston, TX, USA;Division of Clinical Genetics, Children’s Mercy Kansas City, Kansas City, MO, USA;Division of Clinical Genetics, Children’s Mercy Kansas City, Kansas City, MO, USA;The University of Missouri-Kansas City, School of Medicine, Kansas City, MO, USA;GeneDX, Gaithersburg, MD, USA;Genetic Unit, Department of Pediatrics, Fondazione MBBM S. Gerardo Hospital, Monza, Italy;Genetics Department, Cook Children’s Hospital, Fort Worth, TX, USA;Gillette Children’s Specialty Healthcare, Saint Paul, MN, USA;H C Andersen Chilldrens Hospital, Odense University Hospital, Odense, Denmark;INSERM UMR 1231 Génétique des Anomalies du Développement, Université Bourgogne Franche-Comté, Dijon, France;Centre de Référence Maladies Rares « Anomalies du Développement et Syndromes malformatifs »​ Université Bourgogne Franche-Comté, Dijon, France;Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany;Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Kaiser Permanente Southern California, Los Angeles, CA, USA;Laboratorio di Genetica Medica - ASST Papa Giovanni XXIII, Bergamo, Italy;NYU Grossman School of Medicine, Department of Pediatrics, Clinical Genetic Services, New York, NY, USA;Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK;Oasi Research Institute-IRCCS, Troina, Italy;Oregon Health & Science University, Corvallis, OR, USA;Pediatric Neurology, Assuta-Ashdod University Hospital, Ashdod, Israel;Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel;Rare Disease Institute, Children’s National Health System, Washington, DC, USA;School of Medicine and the Robinson Research Institute, the University of Adelaide at the Women’s and Children’s Hospital, Adelaide, South Australia, Australia;Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia;South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia;Sorbonne Universités, Centre de Référence déficiences intellectuelles de causes rares, département de génétique et embryologie médicale, Hôpital Trousseau, AP-HP, Paris, France;The Atwal Clinic: Genomic & Personalized Medicine, Jacksonville, FL, USA;The Permanente Medical Group, Oakland, CA, USA;The University of Missouri-Kansas City, School of Medicine, Kansas City, MO, USA;Children’s Mercy Kansas City, Center for Pediatric Genomic Medicine, Kansas City, MO, USA;UF Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne and INSERM UMR1231 GAD, Université de Bourgogne Franche-Comté, F-21000, Dijon, France;INSERM UMR 1231 Génétique des Anomalies du Développement, Université Bourgogne Franche-Comté, Dijon, France;Unit of Neuromuscular and Neurodegenerative Disorders, Department Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, 00146, Rome, Italy;Àrea de Genètica Clínica i Molecular, Hospital Vall d’Hebrón, Barcelona, Spain;

关键词: Neurodevelopmental disorders;    hnRNPs;    Cortex development;    Gene families;   

DOI  :  10.1186/s13073-021-00870-6

来源: Springer

【 摘 要 】

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

【 授权许可】

CC BY