From focal epilepsy to Dravet syndrome--Heterogeneity of the phenotype due to SCN1A mutations of the p.Arg1596 amino acid residue in the Nav1.1 subunit.

OBJECTIVE: The aim of this study was to analyze the intra-/interfamilial phenotypic heterogeneity due to variants at the highly evolutionary conservative p.Arg1596 residue in the Nav1.1 subunit. MATERIALS/PARTICIPANTS: Among patients referred for analysis of the SCN1A gene one recurrent, heritable mutation was found in families enrolled into the study. Probands from those families even clinically diagnosed with atypical Dravet syndrome (DS), generalized epilepsy with febrile seizures plus (GEFS+), and focal epilepsy, had heterozygous p.Arg1596 His/Cys missense substitutions, c.4787G>T and c.4786C>T in the SCN1A gene. METHOD: Full clinical evaluation, including cognitive development, neurological examination, EEGs, MRI was performed in probands and affected family members in developmental age. The whole SCN1A gene sequencing was performed for all probands. The exon 25, where the identified missense substitutions are localized, was directly analyzed for the other family members. RESULTS: Mutation of the SCN1A p.1596Arg was identified in three families, in one case substitution p.Arg1596Cys and in two cases p.Arg1596His. Both mutations were previously described as pathogenic and causative for DS, GEFS+ and focal epilepsy. Spectrum of phenotypes among presented families with p.Arg1596 mutations shows heterogeneity ranged from asymptomatic cases, through FS and FS+ to GEFS+/Panayiotopoulos syndrome and epilepsies with and without febrile seizures, and epileptic encephalopathy such as DS. Phenotypes differ among patients displaying both focal and generalized epilepsies. Some patients demonstrated additionally Asperger syndrome and ataxia. CONCLUSION: Clinical picture heterogeneity of the patients carrying mutation of the same residue indicates the involvement of the other factors influencing the SCN1A gene mutations' penetrance.

Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders.

Copy-number variants (CNVs) collectively represent an important cause of neurodevelopmental disorders such as developmental delay (DD)/intellectual disability (ID), autism, and epilepsy. In contrast to DD/ID, for which the application of microarray techniques enables detection of pathogenic CNVs in -10-20% of patients, there are only few studies of the role of CNVs in epilepsy and genetic etiology in the vast majority of cases remains unknown. We have applied whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) to a cohort of 102 patients with various types of epilepsy with or without additional neurodevelopmental abnormalities. Chromosomal microarray analysis revealed 24 non-polymorphic CNVs in 23 patients, among which 10 CNVs are known to be clinically relevant. Two rare deletions in 2q24.1q24.3, including KCNJ3 and 9q21.13 are novel pathogenic genetic loci and 12 CNVs are of unknown clinical significance. Our results further support the notion that rare CNVs can cause different types of epilepsy, emphasize the efficiency of detecting novel candidate genes by whole-genome array CGH, and suggest that the clinical application of array CGH should be extended to patients with unexplained epilepsies.

Aicardi-Goutières Syndrome due to a SAMHD1 Mutation Presenting with Deep White Matter Cysts.

We report on the first Polish patient diagnosed with the Aicardi-Goutières syndrome 5 (AGS5). AGS is caused by mutations in one of 9 genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, IFIH, LSM11, RNU7-1) which stimulate the type I interferon response. The diagnosis was confirmed by identifying a compound heterozygous mutation p.(Phe165Ser)/p.(Gln235*) in the SAMHD1 gene using whole-exome sequencing. The cystic lesions in the temporal lobes are an uncommon finding in the presented patient carrying a SAMHD1 mutation. Reporting new cases expands the range of phenotypes and plays the crucial role in understanding the AGS pathogenesis and creates new therapy approaches.

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly.

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.