Phenotypic Spectrum in Individuals With Pathogenic GABRG2 Loss- and Gain-of-Function Variants

BACKGROUND AND OBJECTIVES: gene can lead to highly diverse phenotypes. METHODS: variants. Electroclinical information was systematically collected, and electrophysiologic measurements were conducted for missense variants to explore potential alterations in receptor function. RESULTS: variants (18 null and 17 missense). Functional assessments of the missense variants revealed that 9 caused LoF and 3 caused gain-of-function (GoF). The remaining 5 did not alter receptor function and are likely not pathogenic. Based on functional analysis and electroclinical data, 37 affected individuals were categorized into 3 groups: null LoF, missense LoF, and GoF variants. Among 19 individuals with null variants, epilepsy was diagnosed in 13, with a median onset of 14 months. The remaining 6 of 19 only had febrile seizures. Developmental delay/intellectual disability (DD/ID) was observed in 1 of 19 and psychiatric features in 4 of 18. By contrast, all 12 individuals with missense LoF variants suffered from epilepsy with a median onset of 15 months. Most common epilepsy diagnoses were febrile seizures plus in 4 of 12 and DEE in 4 of 12. DD/ID affected 9 of 12, and psychiatric features were diagnosed in 8 of 12. Statistical comparisons revealed that null variants were associated with a milder phenotype than missense LoF variants. Finally, 5 of 6 individuals with GoF variants had DEE characterized by early infancy onset at 2 months and severe/profound DD/ID. The sixth individual exhibited mild DD/ID and hypotonia without seizures. DISCUSSION: variants depends on the functional consequences of the variants. Null variants are associated with a mild phenotype and missense LoF variants with an intermediate phenotype while GoF variants can lead to severe phenotypes.