By identifying >70 novel homozygous or compound heterozygous genetic variants in 124 patients with CS with different disease severity and ethnic backgrounds, we considerably broaden the and mutation spectrum responsible for CS. Besides providing information relevant for diagnosis of and genetic counselling for this devastating disorder, this study improves the definition of the puzzling genotype-phenotype relationships in patients with CS.

ObjectiveTo provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome.MethodsWe analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations.ResultsA total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations.ConclusionsThese findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.

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Objective: γ-Aminobutyric acid (GABA) A -receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABA A -receptorrelated disorders as a whole and seek possible genotype-phenotype correlations. Methods:We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABA A -receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature. Results:We gathered the reported patients in three epileptic phenotypes: 15 patients with fever-related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABA A -receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes.Significance: GABA A -receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics. K E Y W O R D Schannelopathy, developmental and epileptic encephalopathy, GABA A receptor, genetic generalized epilepsy Key points• γ-Aminobutyric acid (GABA) A -receptor subunit variants lead to a fever-related epilepsy, a generalized epilepsy, or a developmental and epileptic encephalopathy • Phenotype was not associated with a given gene, but with the location of variants within the protein • Variants of the transmembrane domain are significantly more severe than other variants in our cohort and in 402 published cases.

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