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Childhood Onset Schizophrenia is a rare neuropsychiatric disorder significantly associated with 22q11.2 Deletion Syndrome. We describe a male patient, followed from childhood to adolescence, who exhibited premorbid impairments in language, learning and social abilities, along with comorbid anxiety disorders. Over time, he gradually developed Childhood Onset Schizophrenia, with neuroradiological findings of white matter hyperintensities, a dysmorphic corpus callosum and Hippocampal Malrotation. These findings were observed in the context of a genetic diagnosis of 22q11.2 Deletion Syndrome, despite the absence of the most common congenital malformations and clinical conditions typically associated with this syndrome. A remarkable aspect of this case report is the emphasis on the importance of suspecting 22q11.2 Deletion Syndrome even in cases where only the neuropsychiatric phenotype of Childhood-Onset Schizophrenia and structural brain alterations, is present. While abnormalities of white matter and corpus callosum are associated with schizophrenia in patients with 22q11.2 Deletion Syndrome, Hippocampal Malrotation is more frequently described in patients with epilepsy and prolonged febrile seizures. Recently, only 10 adult patients with 22q11.2 Deletion Syndrome have been reported to have Hippocampal Malrotation, six of whom were affected by schizophrenia, with or without epilepsy. Our case report aims to extend the neuroradiological findings associated with 22q11.2 Deletion Syndrome and Schizophrenia, including Hippocampal Malrotation. This is the first case report in which Hippocampal Malrotation has been described in Childhood Onset Schizophrenia and 22q11.2 Deletion Syndrome. We suggest that patients with Hippocampal Malrotation and Childhood Onset Schizophrenia, should have a chromosomal microarray performed to screen for 22q11.2 Deletion Syndrome.

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In recent years, precision medicine has emerged as a new paradigm for improved and more individualized patient care. Its key objective is to provide the right treatment, to the right patient at the right time, by basing medical decisions on individual characteristics, including specific genetic biomarkers. In order to realize this objective researchers and physicians must first identify the underlying genetic cause; over the last 10 years, advances in genetics have made this possible for several monogenic epilepsies. Through next generation techniques, a precise genetic aetiology is attainable in 30-50% of genetic epilepsies beginning in the paediatric age. While committed in such search for novel genes carrying disease-causing variants, progress in the study of experimental models of epilepsy has also provided a better understanding of the mechanisms underlying the condition. Such advances are already being translated into improving care, management and treatment of some patients. Identification of a precise genetic aetiology can already direct physicians to prescribe treatments correcting specific metabolic defects, avoid antiseizure medicines that might aggravate functional consequences of the disease-causing variant or select the drugs that counteract the underlying, genetically determined, functional disturbance. Personalized, tailored treatments should not just focus on how to stop seizures but possibly prevent their onset and cure the disorder, often consisting of seizures and its comorbidities including cognitive, motor and behaviour deficiencies. This review discusses the therapeutic implications following a specific genetic diagnosis and the correlation between genetic findings, pathophysiological mechanisms and tailored seizure treatment, emphasizing the impact on current clinical practice.

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

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