Delineation of a novel neurodevelopmental syndrome associated with PAX5 haploinsufficiency

Human MutationVolume 43, Issue 4 p. 461-470 BRIEF REPORT Delineation of a novel neurodevelopmental syndrome associated with PAX5 haploinsufficiency Yoel Gofin, Yoel Gofin orcid.org/0000-0003-3233-258X Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USASearch for more papers by this authorTianyun Wang, Tianyun Wang orcid.org/0000-0002-5179-087X Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USASearch for more papers by this authorMadelyn A. Gillentine, Madelyn A. Gillentine orcid.org/0000-0002-8989-2214 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA Seattle Children's Hospital, Seattle, Washington, USASearch for more papers by this authorTiana M. Scott, Tiana M. Scott orcid.org/0000-0002-6209-8301 Department of Microbiology and Molecular Biology, College of Life Sciences, Brigham Young University, Provo, Utah, USASearch for more papers by this authorAliska M. Berry, Aliska M. Berry Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USASearch for more papers by this authorMahshid S. Azamian, Mahshid S. Azamian orcid.org/0000-0002-8543-8284 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USASearch for more papers by this authorCasie Genetti, Casie Genetti orcid.org/0000-0003-4173-9947 Department of Pediatrics, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorPankaj B. Agrawal, Pankaj B. Agrawal Department of Pediatrics, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Department of Pediatrics, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorJonathan Picker, Jonathan Picker Department of Pediatrics, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorMonica H. Wojcik, Monica H. Wojcik orcid.org/0000-0002-8162-5031 Department of Pediatrics, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Department of Pediatrics, Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USASearch for more papers by this authorMauricio R. Delgado, Mauricio R. Delgado Department of Neurology, University of Texas Southwestern, Dallas, Texas, USA Scottish Rite for Children, Dallas, Texas, USASearch for more papers by this authorSally A. Lynch, Sally A. Lynch orcid.org/0000-0003-3540-1333 Clinical Genetics, Dublin 1, IrelandSearch for more papers by this authorStephen W. Scherer, Stephen W. Scherer orcid.org/0000-0002-8326-1999 Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorJennifer L. Howe, Jennifer L. Howe Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, CanadaSearch for more papers by this authorCarlos A. Bacino, Carlos A. Bacino orcid.org/0000-0002-4342-5012 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USASearch for more papers by this authorStephanie DiTroia, Stephanie DiTroia orcid.org/0000-0002-6847-6780 Department of Pediatrics, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorGrace E. VanNoy, Grace E. VanNoy orcid.org/0000-0003-1257-9702 Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorAnne O'Donnell-Luria, Anne O'Donnell-Luria orcid.org/0000-0001-6418-9592 Department of Pediatrics, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorSeema R. Lalani, Seema R. Lalani Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USASearch for more papers by this authorWilliam D. Graf, William D. Graf orcid.org/0000-0003-0460-4605 Department of Pediatrics, Division of Neurology, Connecticut Children's, University of Connecticut, Farmington, Connecticut, USASearch for more papers by this authorJill A. Rosenfeld, Jill A. Rosenfeld orcid.org/0000-0001-5664-7987 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Baylor Genetics Laboratory, Houston, Texas, USASearch for more papers by this authorEvan E. Eichler, Evan E. Eichler orcid.org/0000-0002-8246-4014 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USASearch for more papers by this authorRachel K. Earl, Rachel K. Earl Center on Human Development and Disability, University of Washington, Seattle, Washington, USA Seattle Children's Autism Center, Seattle, Washington, USA Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USASearch for more papers by this authorDaryl A. Scott, Corresponding Author Daryl A. Scott dscott@bcm.edu orcid.org/0000-0003-1460-5169 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USA Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA Correspondence Daryl A. Scott, Department of Molecular and Human Genetics, Baylor College of Medicine, R813, One Baylor Plaza, BCM225, Houston, TX 770303, USA. Email: dscott@bcm.eduSearch for more papers by this author Yoel Gofin, Yoel Gofin orcid.org/0000-0003-3233-258X Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USASearch for more papers by this authorTianyun Wang, Tianyun Wang orcid.org/0000-0002-5179-087X Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USASearch for more papers by this authorMadelyn A. Gillentine, Madelyn A. Gillentine orcid.org/0000-0002-8989-2214 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA Seattle Children's Hospital, Seattle, Washington, USASearch for more papers by this authorTiana M. Scott, Tiana M. Scott orcid.org/0000-0002-6209-8301 Department of Microbiology and Molecular Biology, College of Life Sciences, Brigham Young University, Provo, Utah, USASearch for more papers by this authorAliska M. Berry, Aliska M. Berry Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USASearch for more papers by this authorMahshid S. Azamian, Mahshid S. Azamian orcid.org/0000-0002-8543-8284 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USASearch for more papers by this authorCasie Genetti, Casie Genetti orcid.org/0000-0003-4173-9947 Department of Pediatrics, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorPankaj B. Agrawal, Pankaj B. Agrawal Department of Pediatrics, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Department of Pediatrics, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorJonathan Picker, Jonathan Picker Department of Pediatrics, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorMonica H. Wojcik, Monica H. Wojcik orcid.org/0000-0002-8162-5031 Department of Pediatrics, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Department of Pediatrics, Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USASearch for more papers by this authorMauricio R. Delgado, Mauricio R. Delgado Department of Neurology, University of Texas Southwestern, Dallas, Texas, USA Scottish Rite for Children, Dallas, Texas, USASearch for more papers by this authorSally A. Lynch, Sally A. Lynch orcid.org/0000-0003-3540-1333 Clinical Genetics, Dublin 1, IrelandSearch for more papers by this authorStephen W. Scherer, Stephen W. Scherer orcid.org/0000-0002-8326-1999 Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorJennifer L. Howe, Jennifer L. Howe Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, CanadaSearch for more papers by this authorCarlos A. Bacino, Carlos A. Bacino orcid.org/0000-0002-4342-5012 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USASearch for more papers by this authorStephanie DiTroia, Stephanie DiTroia orcid.org/0000-0002-6847-6780 Department of Pediatrics, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorGrace E. VanNoy, Grace E. VanNoy orcid.org/0000-0003-1257-9702 Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorAnne O'Donnell-Luria, Anne O'Donnell-Luria orcid.org/0000-0001-6418-9592 Department of Pediatrics, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USASearch for more papers by this authorSeema R. Lalani, Seema R. Lalani Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USASearch for more papers by this authorWilliam D. Graf, William D. Graf orcid.org/0000-0003-0460-4605 Department of Pediatrics, Division of Neurology, Connecticut Children's, University of Connecticut, Farmington, Connecticut, USASearch for more papers by this authorJill A. Rosenfeld, Jill A. Rosenfeld orcid.org/0000-0001-5664-7987 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Baylor Genetics Laboratory, Houston, Texas, USASearch for more papers by this authorEvan E. Eichler, Evan E. Eichler orcid.org/0000-0002-8246-4014 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USASearch for more papers by this authorRachel K. Earl, Rachel K. Earl Center on Human Development and Disability, University of Washington, Seattle, Washington, USA Seattle Children's Autism Center, Seattle, Washington, USA Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USASearch for more papers by this authorDaryl A. Scott, Corresponding Author Daryl A. Scott dscott@bcm.edu orcid.org/0000-0003-1460-5169 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA Texas Children's Hospital, Houston, Texas, USA Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA Correspondence Daryl A. Scott, Department of Molecular and Human Genetics, Baylor College of Medicine, R813, One Baylor Plaza, BCM225, Houston, TX 770303, USA. Email: dscott@bcm.eduSearch for more papers by this author First published: 18 January 2022 https://doi.org/10.1002/humu.24332Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract PAX5 is a transcription factor associated with abnormal posterior midbrain and cerebellum development in mice. PAX5 is highly loss-of-function intolerant and missense constrained, and has been identified as a candidate gene for autism spectrum disorder (ASD). We describe 16 individuals from 12 families who carry deletions involving PAX5 and surrounding genes, de novo frameshift variants that are likely to trigger nonsense-mediated mRNA decay, a rare stop-gain variant, or missense variants that affect conserved amino acid residues. Four of these individuals were published previously but without detailed clinical descriptions. All these individuals have been diagnosed with one or more neurodevelopmental phenotypes including delayed developmental milestones (DD), intellectual disability (ID), and/or ASD. Seizures were documented in four individuals. No recurrent patterns of brain magnetic resonance imaging (MRI) findings, structural birth defects, or dysmorphic features were observed. Our findings suggest that PAX5 haploinsufficiency causes a neurodevelopmental disorder whose cardinal features include DD, variable ID, and/or ASD. Open Research DATA AVAILABILITY STATEMENT All previously unreported variants described in this manuscript have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). Citing Literature Supporting Information Filename Description humu24332-sup-0001-Supp_Mat.pdf160.2 KB Supporting information. humu24332-sup-0002-Supplement_Table_1_11_10_2021.xlsx17.5 KB Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume43, Issue4April 2022Pages 461-470 RelatedInformation