@article{9f21244c8f8c4e528d50ddfd074031c7,
title = "Polymicrogyria is Associated With Pathogenic Variants in PTEN",
abstract = "Objective: Congenital structural brain malformations have been described in patients with pathogenic phosphatase and tensin homologue (PTEN) variants, but the frequency of cortical malformations in patients with PTEN variants and their impact on clinical phenotype are not well understood. Our goal was to systematically characterize brain malformations in patients with PTEN variants and assess the relevance of their brain malformations to clinical presentation. Methods: We systematically searched a local radiology database for patients with PTEN variants who had available brain magnetic resonance imaging (MRI). The MRI scans were reviewed systematically for cortical abnormalities. We reviewed electroencephalogram (EEG) data and evaluated the electronic medical record for evidence of epilepsy and developmental delay. Results: In total, we identified 22 patients with PTEN pathogenic variants for which brain MRIs were available (age range 0.4–17 years). Twelve among these 22 patients (54%) had polymicrogyria (PMG). Variants associated with PMG or atypical gyration encoded regions of the phosphatase or C2 domains of PTEN. Interestingly, epilepsy was present in only 2 of the 12 patients with PMG. We found a trend toward higher rates of global developmental delay (GDD), intellectual disability (ID), and motor delay in individuals with cortical abnormalities, although cohort size limited statistical significance. Interpretation: Malformations of cortical development, PMG in particular, represent an under-recognized phenotype associated with PTEN pathogenic variants and may have an association with cognitive and motor delays. Epilepsy was infrequent compared to the previously reported high risk of epilepsy in patients with PMG. ANN NEUROL 2020;88:1153–1164.",
author = "{the Brain Development Study Group} and Shao, {Diane D.} and Achkar, {Christelle M.} and Abbe Lai and Siddharth Srivastava and Doan, {Ryan N.} and Rodan, {Lance H.} and Chen, {Allen Y.} and Annapurna Poduri and Edward Yang and Walsh, {Christopher A.} and Irons, {Mira B.} and Johnson, {Ervin L.} and Ojeda, {Mayra Martinez} and Olson, {Heather E.} and Mustafa Sahin and Stredny, {Coral M.} and Tan, {Wen Hann}",
note = "Funding Information: The authors are sincerely indebted to the generosity of the families and patients in PTEN clinics across the United States who contributed their time and effort to this study. We would also like to thank the PTEN Hamartoma Syndrome Foundation and the PTEN Research Foundation for their continued support in PTEN research. Connor J. Kenny provided technical assistance for PMG genetic sequencing panel. We thank the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) for exome sequencing and analysis. The Broad CMG was funded 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. C.A.W. is supported by National Institute of Neurologic Disorders and Stroke (NINDS) (RO1 35129) and is an Investigator of the Howard Hughes Medical Institute. A.P. is supported by the Boston Children's Hospital Translational Research Program. D.D.S. is supported by Neurology Resident Research Education Program R25NS070682. H.E.O. is supported by the NINDS (K23 NS107646-02, PI Olson). S.S. is supported by The Developmental Synaptopathies Consortium (U54NS092090), which is part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). The Developmental Synaptopathies Consortium (U54NS092090) is part of the RDCRN, an initiative of the Office of Rare Diseases Research (ORDR), NCATS. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). Funding Information: The authors are sincerely indebted to the generosity of the families and patients in PTEN clinics across the United States who contributed their time and effort to this study. We would also like to thank the PTEN Hamartoma Syndrome Foundation and the PTEN Research Foundation for their continued support in PTEN research. Connor J. Kenny provided technical assistance for PMG genetic sequencing panel. We thank the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) for exome sequencing and analysis. The Broad CMG was funded 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. C.A.W. is supported by National Institute of Neurologic Disorders and Stroke (NINDS) (RO1 35129) and is an Investigator of the Howard Hughes Medical Institute. A.P. is supported by the Boston Children's Hospital Translational Research Program. D.D.S. is supported by Neurology Resident Research Education Program R25NS070682. H.E.O. is supported by the NINDS (K23 NS107646‐02, PI Olson). S.S. is supported by The Developmental Synaptopathies Consortium (U54NS092090), which is part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). The Developmental Synaptopathies Consortium (U54NS092090) is part of the RDCRN, an initiative of the Office of Rare Diseases Research (ORDR), NCATS. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). Publisher Copyright: {\textcopyright} 2020 American Neurological Association",
year = "2020",
month = dec,
doi = "10.1002/ana.25904",
language = "English (US)",
volume = "88",
pages = "1153--1164",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "6",
}