Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation
| Autor: | Leah J. Smith, Joy Jayaseelan, Mauricio R. Delgado, Ingrid Cristian, Pengfei Liu, Naomi Meeks, James R. Lupski, Jill A. Rosenfeld, Donna M. Muzny, Lynn Pais, Michael M. Khayat, Craig D. Kaplan, Qingchang Meng, Devon Haynes, Susan M. White, Payal Arora, Stephanie DiTroia, Linda Z. Rossetti, Andrea M. Lewis, Marie-Claude Gingras, Davut Pehlivan, Richard A. Gibbs, Michael F. Wangler, Adam W. Hansen |
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| Rok vydání: | 2021 |
| Předmět: |
Genetics
Ataxia POLR2A QH426-470 Biology medicine.disease Short stature Article Hypotonia Frameshift mutation Developmental disorder Germline mutation Neurodevelopmental disorder phenotypic expansion Pol II medicine Molecular Medicine Missense mutation RNA polymerase II Mendelian disease medicine.symptom developmental disorder Genetics (clinical) |
| Zdroj: | HGG advances HGG Advances, Vol 2, Iss 1, Pp 100014-(2021) |
| ISSN: | 2666-2477 |
| DOI: | 10.1016/j.xhgg.2020.100014 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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