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

Abbe Lai; Aubrie Soucy; Christelle Moufawad El Achkar; Anthony J Barkovich; Yang Cao; Marina DiStefano; Michael Evenson; Renzo Guerrini; Devon Knight; Yi-Shan Lee; Heather C Mefford; David T Miller; Ghayda Mirzaa; Ganesh Mochida; Lance H Rodan; Mayher Patel; Lacey Smith; Sara Spencer; Christopher A Walsh; Edward Yang; Christopher J Yuskaitis; Timothy Yu; Annapurna Poduri; ClinGen Brain Malformation Variant Curation Expert Panel

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

Genet Med. 2022 Nov;24(11):2240-2248. doi: 10.1016/j.gim.2022.07.020. Epub 2022 Aug 23.

Authors

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

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain* / pathology
Class I Phosphatidylinositol 3-Kinases / genetics
Congenital Abnormalities* / genetics
Genetic Testing
Genetic Variation* / genetics
Genome, Human*
Humans
Mutation
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt / genetics
TOR Serine-Threonine Kinases / genetics

Substances

AKT3 protein, human
Class I Phosphatidylinositol 3-Kinases
MTOR protein, human
Phosphatidylinositol 3-Kinases
phosphoinositol-3 kinase regulatory subunit 2, human
PIK3CA protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding