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

Abbe Lai1, Aubrie Soucy2, Christelle Moufawad El Achkar3

  • 1Division 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.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|August 23, 2022
PubMed
Abstract

Insights

Classifying somatic variants in mTOR pathway genes is vital for developmental disorders. This study adapted guidelines to accurately interpret these unique genetic variations, improving diagnosis for affected individuals.

Area of Science:

  • Genetics
  • Developmental Biology
  • Molecular Pathology

Background:

  • Postzygotic (somatic) variants in mTOR pathway genes lead to diverse developmental abnormalities.
  • Accurate classification of these somatic variants is critical for patient diagnosis and family counseling.
  • Existing guidelines primarily address germline variants, necessitating adaptation for somatic variations.

Purpose of the Study:

  • To curate somatic variants associated with developmental brain malformations.
  • To adapt and specify existing guidelines for interpreting somatic variants in key mTOR pathway genes (AKT3, MTOR, PIK3CA, PIK3R2).

Main Methods:

  • Formation of the ClinGen Brain Malformation Variant Curation Expert Panel.
  • Selection of AKT3, MTOR, PIK3CA, and PIK3R2 genes for focused curation.
  • Modification of 24 out of 28 established American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria.

Main Results:

  • Developed novel approaches for somatic variant interpretation, including using variant allele fraction (VAF) differences as a proxy for de novo variation.
  • Integrated both somatic and germline evidence for more robust variant classification.
  • Incorporated variable tissue expression to delineate phenotypes associated with somatic variants.

Conclusions:

  • Established a framework for the rigorous interpretation of somatic mosaic variants.
  • The developed framework addresses challenges unique to somatic variants.
  • This approach is broadly applicable to numerous genes and conditions involving somatic variants.
Keywords:
AKT3MTORPIK3CAPIK3R2Somatic mosaicism

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