Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype

Abstract

Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c0.316 G > A; p.A106T) in the GABRG2 gene that was identified in five unrelated individuals. These patients were described to have a more severe phenotype than previously reported for GABRG2 missense variants. Common features include variable early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features and vision/ocular issues. Our report further explores a recurrent pathogenic missense variant within the GABRG2 variant family and broadens the spectrum of associated phenotypes for GABRG2-associated disorders.

Keywords:

• Epilepsy
• genetics
• seizures
• GABRG2
• phenotype
• missense

Acknowledgements

We wish to acknowledge the collaborations with our patients and their families, who consented to share their stories in an effort to add to the published information on epilepsy genes.

Disclosure statement

GeneDx employee authors (F Zou, K McWalter, L Schmidt, A Decker, A Shanmugham, E Butler, G Richard, and D McKnight): In accordance with Taylor & Francis policy and our ethical obligation as researchers, we report that we are employees of GeneDx, Inc., a wholly-owned subsidiary of OPKO Health, Inc., a company that may be affected by the research reported in the enclosed paper. We have disclosed those interests fully to Taylor & Francis, and have in place an approved plan for managing any potential conflicts arising from that employment.

Jonathan Picker MBChB, PhD: In accordance with Taylor & Francis policy and my ethical obligation as a researcher, I report that I have business interests as a founding member and major shareholder in Global Gene Corporation. This company is involved in collecting Data in India and thus is unlikely to be affected by the research reported in the enclosed paper.

Livija Medne, MS, CGC: In accordance with Taylor & Francis policy and my ethical obligation as a researcher, I report that I am on the Sanofi Genzyme Advisory Board: Next Generation Sequencing and Variant Interpretation.

No potential conflict of interest was reported by the remaining authors.

Additional information

Funding

Center for Integrated Approaches to Undiagnosed Diseases (supports Dr. David A. Sweetser) [1U01HG007690], and The Bryan and Caris Chan Family Foundation (supports Dr. Raymond Y. Wang).