@article{46c34afc05b740c688646c73d4ef86fb,
title = "Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation",
abstract = "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.",
keywords = "Mendelian disease, POLR2A, Pol II, RNA polymerase II, RNAPII, RPB1, developmental disorder, genocentric, phenotypic expansion, transcriptopathy",
author = "Hansen, {Adam W.} and Payal Arora and Khayat, {Michael M.} and Smith, {Leah J.} and Lewis, {Andrea M.} and Rossetti, {Linda Z.} and Joy Jayaseelan and Ingrid Cristian and Devon Haynes and Stephanie DiTroia and Naomi Meeks and Delgado, {Mauricio R.} and Rosenfeld, {Jill A.} and Lynn Pais and White, {Susan M.} and Qingchang Meng and Davut Pehlivan and Pengfei Liu and Gingras, {Marie Claude} and Wangler, {Michael F.} and Muzny, {Donna M.} and Lupski, {James R.} and Kaplan, {Craig D.} and Gibbs, {Richard A.}",
note = "Funding Information: This work was supported in part by grants UM1 HG008898 from the National Human Genome Research Institute (NHGRI) to the Baylor College of Medicine Center for Common Disease Genetics and UM1 HG006542 from the National Heart, Lung, and Blood Institute (NHLBI) and NHGRI to the Baylor Hopkins Center for Mendelian Genomics. C.D.K. was supported by grants R01 GM097260 and R01 GM120450 National Institute of General Medical Sciences (NIGMS). A.W.H. was supported in part by NIH T32 GM08307-26 , The Cullen Foundation , and the Baylor College of Medicine President{\textquoteright}s Circle . D.P. was supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology (AAN), American Brain Foundation (ABF) and Muscle Study Group (MSG), and the International Rett Syndrome Foundation (IRSF grant #3701-1 ). S.M.W. is supported by the Victorian Government{\textquoteright}s Operational Infrastructure Support Program . S.D. was supported by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141 . We thank Ali Jalali and Amy L. McGuire for the valuable discussions. Last, we thank the individuals participating in research and their families for their assistance and significant contributions to this research. Funding Information: This work was supported in part by grants UM1 HG008898 from the National Human Genome Research Institute (NHGRI) to the Baylor College of Medicine Center for Common Disease Genetics and UM1 HG006542 from the National Heart, Lung, and Blood Institute (NHLBI) and NHGRI to the Baylor Hopkins Center for Mendelian Genomics. C.D.K. was supported by grants R01 GM097260 and R01 GM120450 National Institute of General Medical Sciences (NIGMS). A.W.H. was supported in part by NIH T32 GM08307-26, The Cullen Foundation, and the Baylor College of Medicine President's Circle. D.P. was supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology (AAN), American Brain Foundation (ABF) and Muscle Study Group (MSG), and the International Rett Syndrome Foundation (IRSF grant #3701-1). S.M.W. is supported by the Victorian Government's Operational Infrastructure Support Program. S.D. was supported by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. We thank Ali Jalali and Amy L. McGuire for the valuable discussions. Last, we thank the individuals participating in research and their families for their assistance and significant contributions to this research. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical genetic testing offered in the Baylor Genetics Laboratory. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2021",
month = jan,
day = "14",
doi = "10.1016/j.xhgg.2020.100014",
language = "English (US)",
volume = "2",
journal = "Human Genetics and Genomics Advances",
issn = "2666-2477",
publisher = "Cell Press",
number = "1",
}