Intrafamilial neurological phenotypic variability due to either biallelic or monoallelic pathogenic variants in .

Pathogenic heterozygous variants in are associated with familial hemiplegic migraine, episodic ataxia type 2 and spinocerebellar ataxia type 6, and more recently, neurodevelopmental disorders. We describe a severe, early-onset phenotype including severe muscular hypotonia, early-onset epileptic seizures, apnoea, optic atrophy and dysphagia in three siblings carrying compound heterozygous frameshift variants in . Two male patients died at the age of 5 or 14 months of suspected SIDS or severe developmental epileptic encephalopathy (DEE) with refractory seizures and apnoea. A male child (index patient) developed severe early-onset DEE including seizures and ictal apnoea at the age of 4 weeks. Another male child developed generalized epilepsy and mild intellectual impairment in late infancy, and his mother and his maternal uncle were identified as carriers of a known pathogenic variant [c.2602delG heterozygous, p. (Ala868Profs24)] with a diagnosis of episodic ataxia type 2. This maternal pathogenic variant c.2602delG was detected in the index patient and child 2. Trio-Exome sequencing identified an additional heterozygous pathogenic variant in the gene, c.5476delC, p.(His1826Thrfs30) in the index patient and child 2, which was inherited from the asymptomatic father. In conclusion, the novel compound heterozygosity for two frameshift pathogenic variants, maternally [c.2602delG, p.(Ala868Profs24)] and paternally [c.5476delC, p.(His1826Thrfs3)] is associated with a severe phenotype of early-onset DEE. This observation highlights the necessity of additional analyses to clarify unusual phenotypes even if a pathogenic variant has already been identified, and expands the clinical spectrum of -related disorders.