Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation
Adam W. Hansen,
Payal Arora,
Michael M. Khayat,
Leah J. Smith,
Andrea M. Lewis,
Linda Z. Rossetti,
Joy Jayaseelan,
Ingrid Cristian,
Devon Haynes,
Stephanie DiTroia,
Naomi Meeks,
Mauricio R. Delgado,
Jill A. Rosenfeld,
Lynn Pais,
Susan M. White,
Qingchang Meng,
Davut Pehlivan,
Pengfei Liu,
Marie-Claude Gingras,
Michael F. Wangler,
Donna M. Muzny,
James R. Lupski,
Craig D. Kaplan,
Richard A. Gibbs
Affiliations
Adam W. Hansen
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Corresponding author
Payal Arora
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
Michael M. Khayat
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Leah J. Smith
Department of Biochemistry and Biophysics, Texas A&M University, TX, USA
Andrea M. Lewis
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Linda Z. Rossetti
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Joy Jayaseelan
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
Ingrid Cristian
Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL, USA
Devon Haynes
Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL, USA
Stephanie DiTroia
Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Naomi Meeks
Departments of Pediatrics and Genetics, University of Colorado School of Medicine, Aurora, CO, USA
Mauricio R. Delgado
Texas Scottish Rite Hospital for Children, Dallas, TX, USA; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Jill A. Rosenfeld
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics Laboratories, Houston, TX, USA
Lynn Pais
Broad Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Susan M. White
Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Parkville 3052, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
Qingchang Meng
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
Davut Pehlivan
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Pengfei Liu
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics Laboratories, Houston, TX, USA
Marie-Claude Gingras
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
Michael F. Wangler
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA
Donna M. Muzny
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
James R. Lupski
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children’s Hospital, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Craig D. Kaplan
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Corresponding author
Richard A. Gibbs
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Summary: De novo germline variation in POLR2A was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic de novo or inherited variants in POLR2A, detail their phenotypes, and map all known variants to the domain structure of POLR2A and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by de novo missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance—with yeast functional assays further supporting altered function—one affected by a de novo in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). POLR2A-related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.
