. 2022 Nov;24(11):2240-2248.

doi: 10.1016/j.gim.2022.07.020. Epub 2022 Aug 23.

The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2

Abbe Lai¹, Aubrie Soucy², Christelle Moufawad El Achkar³, Anthony J Barkovich⁴, Yang Cao⁵, Marina DiStefano⁶, Michael Evenson⁵, Renzo Guerrini⁷, Devon Knight⁸, Yi-Shan Lee⁵, Heather C Mefford⁹, David T Miller², Ghayda Mirzaa¹⁰, Ganesh Mochida², Lance H Rodan¹¹, Mayher Patel¹², Lacey Smith⁸, Sara Spencer¹³, Christopher A Walsh¹⁴, Edward Yang¹⁵, Christopher J Yuskaitis³, Timothy Yu¹⁶, Annapurna Poduri¹⁷; ClinGen Brain Malformation Variant Curation Expert Panel

Collaborators, Affiliations

Collaborators

ClinGen Brain Malformation Variant Curation Expert Panel:
Christelle Achkar, James Barkovich, Yang Cao, Jamel Chelly, Marina DiStefano, Elizabeth Engle, Michael Evenson, Renzo Guerrini, William Hong, Hyunyong Koh, Devon Knight, Abbe Lai, Rhonda Lassiter, Yi-Shan Lee, Eric Marsh, Heather C Mefford, David T Miller, Ghayda Mirzaa, Ganesh Mochida, Rebecca Pinsky, Annapurna Poduri, Lance H Rodan, Mayher Patel, Catherine Shain, Lacey Smith, Aubrie Soucy, Sara Spencer, Christopher A Walsh, Edward Yang, Timothy Yu, Bo Yuan, Christopher Yuskaitis

Affiliations

¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA.
² Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA.
³ Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA.
⁴ Department of Radiology, University of California, San Francisco, CA.
⁵ Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA; Precision Health Program, Geisinger, Danville, PA.
⁷ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Department of Neuroscience, Meyer Children's University Hospital, University of Florence, Florence, Italy.
⁸ Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA.
⁹ Center for Pediatric Neurological Disease Research, St. Jude Hospital, Memphis, TN.
¹⁰ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA; Department of Pediatrics, University of Washington, Seattle, WA.
¹¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA.
¹³ Division of Reproductive Genetics, Northwestern Medicine, Chicago, IL.
¹⁴ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA.
¹⁵ Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA.
¹⁶ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA. Electronic address: timothy.yu@childrens.harvard.edu.
¹⁷ Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA. Electronic address: annapurna.poduri@childrens.harvard.edu.

PMID: 35997716
PMCID: PMC9883838
DOI: 10.1016/j.gim.2022.07.020

The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2

Abbe Lai et al. Genet Med. 2022 Nov.

. 2022 Nov;24(11):2240-2248.

doi: 10.1016/j.gim.2022.07.020. Epub 2022 Aug 23.

Authors

Collaborators

ClinGen Brain Malformation Variant Curation Expert Panel:
Christelle Achkar, James Barkovich, Yang Cao, Jamel Chelly, Marina DiStefano, Elizabeth Engle, Michael Evenson, Renzo Guerrini, William Hong, Hyunyong Koh, Devon Knight, Abbe Lai, Rhonda Lassiter, Yi-Shan Lee, Eric Marsh, Heather C Mefford, David T Miller, Ghayda Mirzaa, Ganesh Mochida, Rebecca Pinsky, Annapurna Poduri, Lance H Rodan, Mayher Patel, Catherine Shain, Lacey Smith, Aubrie Soucy, Sara Spencer, Christopher A Walsh, Edward Yang, Timothy Yu, Bo Yuan, Christopher Yuskaitis

Affiliations

¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA.
² Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA.
³ Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA.
⁴ Department of Radiology, University of California, San Francisco, CA.
⁵ Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA; Precision Health Program, Geisinger, Danville, PA.
⁷ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Department of Neuroscience, Meyer Children's University Hospital, University of Florence, Florence, Italy.
⁸ Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA.
⁹ Center for Pediatric Neurological Disease Research, St. Jude Hospital, Memphis, TN.
¹⁰ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA; Department of Pediatrics, University of Washington, Seattle, WA.
¹¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA.
¹³ Division of Reproductive Genetics, Northwestern Medicine, Chicago, IL.
¹⁴ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA.
¹⁵ Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA.
¹⁶ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA. Electronic address: timothy.yu@childrens.harvard.edu.
¹⁷ Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA. Electronic address: annapurna.poduri@childrens.harvard.edu.

PMID: 35997716
PMCID: PMC9883838
DOI: 10.1016/j.gim.2022.07.020

Abstract

Purpose: Postzygotic (somatic) variants in the mTOR pathway genes cause a spectrum of distinct developmental abnormalities. Accurate classification of somatic variants in this group of disorders is crucial for affected individuals and their families.

Methods: The ClinGen Brain Malformation Variant Curation Expert Panel was formed to curate somatic variants associated with developmental brain malformations. We selected the genes AKT3, MTOR, PIK3CA, and PIK3R2 as the first set of genes to provide additional specifications to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) sequence variant interpretation guidelines, which currently focus solely on germline variants.

Results: A total of 24 of the original 28 ACMG/AMP criteria required modification. Several modifications used could be applied to other genes and disorders in which somatic variants play a role: 1) using variant allele fraction differences as evidence that somatic mutagenesis occurred as a proxy for de novo variation, 2) incorporating both somatic and germline evidence, and 3) delineating phenotype on the basis of variable tissue expression.

Conclusion: We have established a framework for rigorous interpretation of somatic mosaic variants, addressing issues unique to somatic variants that will be applicable to many genes and conditions.

Keywords: AKT3; MTOR; PIK3CA; PIK3R2; Somatic mosaicism.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest D.T.M. has received honoraria from Ambry Genetics and PreventionGenetics. All other authors declare no conflicts of interest.

References

1. Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A developmental and genetic classification for malformations of cortical development: update 2012. Brain. 2012;135(Pt 5):1348–1369. 10.1093/brain/aws019 - DOI - PMC - PubMed
1. Severino M, Geraldo AF, Utz N, et al. Definitions and classification of malformations of cortical development: practical guidelines. Brain. 2020;143(10):2874–2894. Published correction appears in Brain. 2020;143(12):e108. 10.1093/brain/awaa174 - DOI - PMC - PubMed
1. Poduri A, Evrony GD, Cai X, et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron. 2012; 74(1):41–48. 10.1016/j.neuron.2012.03.010 - DOI - PMC - PubMed
1. Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 2012;44(8):941–945. 10.1038/ng.2329 - DOI - PMC - PubMed
1. Murugan AK, Alzahrani A, Xing M. Mutations in critical domains confer the human mTOR gene strong tumorigenicity. J Biol Chem. 2013;288(9):6511–6521. 10.1074/jbc.M112.399485 - DOI - PMC - PubMed

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The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2

Collaborators

Affiliations

The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous