P 1001. A Pathogenic GABRB3 Variant Is Associated with Cleft Palate in a Patient with Epileptic Encephalopathy

Background: Mutations in GABA receptor subunit genes have been associated with a wide spectrum of epilepsies from mild generalized epilepsies to epileptic encephalopathies (EE). GABA_A receptors are ligand-gated ion channels, mediating postsynaptic inhibition. The phenotypic spectrum of epilepsies in patients with GABRB3 mutations has been recently described. To date, specific dysmorphic features in GABRB3 patients were not reported. Yet, there are several lines of evidence indicating that cleft palates may be a dysmorphic feature in patients with epilepsy and GABA receptor mutations. We report the first patient with EE associated with a GABRB3 mutation who additionally presented with a cleft palate.

Aims: Our report broadens the clinical spectrum of GABRB3-associated epilepsies and aims at sensitizing for cleft palates in patients with epilepsy and mutations in GABA receptor subunits.

Methods: Whole exome sequencing was performed in our patient with EE and cleft palate. Sanger sequencing of both parents was performed for the GABRB3 variant of the index.

Results: We report a boy presenting with encephalopathy manifesting with therapy-refractory seizures from the first day of life onward. Initial electroencephalogram (EEG) recording showed a burst suppression pattern, an early postnatal cranial magnetic resonance imaging (MRI) was unremarkable. On follow-up, severe neurodevelopmental delay was observed, and hypsarrhythmia was identified in the EEG. At 6 months of age, MRI showed a generalized hypomyelination and a thin corpus callosum. Of note, the patient additionally presented with a cleft palate. Extensive metabolic testing and karyogram proved unrevealing. Through whole exome sequencing, we identified a novel heterozygous de novo mutation in GABRB3 (c.899T>C (p.I300T)). This mutation has not been reported in exome variant server (ExAC), gnomAD and 1,000 genomes databases nor in ClinVar. Given that neighboring variants in GABRB3 have previously been associated with EE, the pathogenic relevance of this de novo variant regarding the EE in our patient was very likely.

Conclusion: We present a boy with EE and a cleft palate associated with a mutation in GABRB3. While complete knockout of GABRB3 is associated with EE and cleft palate in mice, reports about human individuals with such a GABRB3-associated phenotype are lacking to date. Notably, all homozygous GABRB3 null mouse mutants presenting with cleft palate died immediately after birth, while heterozygous GABRB3 mice show a milder phenotype with a cleft palate only in very few cases. This might resemble the human phenotype, presuming that human embryos with homozygous GABRB3 mutations may die prenatally. A few months ago, Niaudet et al reported for the first time two families with mutations in another GABA_A receptor, GABRA3, which were associated with orofacial dysmorphies such as micrognathia or cleft palate in addition to their severe epilepsy. Given the sum of these data, we suggest that the cleft palate in our patient is indeed part of the GABRB3 clinical spectrum.