Case Report: Phenotype-Driven Diagnosis of Atypical Dravet-Like Syndrome Caused by a Novel Splicing Variant in the SCN2A Gene.

Febrile-associated epileptic encephalopathy is a large genetically heterogeneous group that is associated with pathogenic variants in SCN1A, PCDH19, SCN2A, SCN8A, and other genes. The disease onset ranges from neonatal or early-onset epileptic encephalopathy to late-onset epilepsy after 18 months. Some etiology-specific epileptic encephalopathies have target therapy which can serve as a clue for the correct genetic diagnosis. We present genetic, clinical, electroencephalographic, and behavioral features of a 4-year-old girl with epileptic encephalopathy related to a de novo intronic variant in the SCN2A gene. Initial NGS analysis revealed a frameshift variant in the KDM6A gene and a previously reported missense variant in SCN1A. Due to lack of typical clinical signs of Kabuki syndrome, we performed X-chromosome inactivation that revealed nearly complete skewed inactivation. Segregation analysis showed that the SCN1A variant was inherited from a healthy father. The proband had resistance to multiple antiseizure medications but responded well to sodium channel inhibitor Carbamazepine. Reanalysis of NGS data by a neurogeneticist revealed a previously uncharacterized heterozygous variant c.1035-7A>G in the SCN2A gene. Minigene assay showed that the c.1035-7A>G variant activates a cryptic intronic acceptor site which leads to 6-nucleotide extension of exon 9 (NP_066287.2:p.(Gly345_Gln346insTyrSer). SCN2A encephalopathy is a recognizable severe phenotype. Its electro-clinical and treatment response features can serve as a hallmark. In such a patient, reanalysis of genetic data is strongly recommended in case of negative or conflicting results of DNA analysis.

Long contiguous stretches of homozygosity spanning shortly the imprinted loci are associated with intellectual disability, autism and/or epilepsy.

BACKGROUND: Long contiguous stretches of homozygosity (LCSH) (regions/runs of homozygosity) are repeatedly detected by single-nucleotide polymorphism (SNP) chromosomal microarrays. Providing important clues regarding parental relatedness (consanguinity), uniparental disomy, chromosomal recombination or rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Additionally, despite being relevant to imprinting, LCSH at imprinted loci have not been truly addressed in terms of pathogenicity. In this study, we examined LCSH in children with unexplained intellectual disability, autism, congenital malformations and/or epilepsy focusing on chromosomal regions which harbor imprinted disease genes. RESULTS: Out of 267 cases, 14 (5.2 %) were found to have LCSH at imprinted loci associated with a clinical outcome. There were 5 cases of LCSH at 15p11.2, 4 cases of LCSH at 7q31.2, 3 cases of LCSH at 11p15.5, and 2 cases of LCSH at 7q21.3. Apart from a case of LCSH at 7q31.33q32.3 (~4 Mb in size), all causative LCSH were 1-1.5 Mb in size. Clinically, these cases were characterized by a weak resemblance to corresponding imprinting diseases (i.e., Silver-Russell, Beckwith-Wiedemann, and Prader-Willi/Angelman syndromes), exhibiting distinctive intellectual disability, autistic behavior, developmental delay, seizures and/or facial dysmorphisms. Parental consanguinity was detected in 8 cases (3 %), and these cases did not exhibit LCSH at imprinted loci. CONCLUSIONS: This study demonstrates that shorter LCSH at chromosomes 7q21.3, 7q31.2, 11p15.5, and 15p11.2 occur with a frequency of about 5 % in the children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations appears to be the most common one among children with neurodevelopmental diseases. Finally, since LCSH less than 2.5-10 Mb in size are generally ignored in diagnostic SNP microarray studies, one can conclude that an important epigenetic cause of intellectual disability, autism or epilepsy is actually overlooked.

Genomic Copy Number Variation Affecting Genes Involved in the Cell Cycle Pathway: Implications for Somatic Mosaicism.

Somatic genome variations (mosaicism) seem to represent a common mechanism for human intercellular/interindividual diversity in health and disease. However, origins and mechanisms of somatic mosaicism remain a matter of conjecture. Recently, it has been hypothesized that zygotic genomic variation naturally occurring in humans is likely to predispose to nonheritable genetic changes (aneuploidy) acquired during the lifetime through affecting cell cycle regulation, genome stability maintenance, and related pathways. Here, we have evaluated genomic copy number variation (CNV) in genes implicated in the cell cycle pathway (according to Kyoto Encyclopedia of Genes and Genomes/KEGG) within a cohort of patients with intellectual disability, autism, and/or epilepsy, in which the phenotype was not associated with genomic rearrangements altering this pathway. Benign CNVs affecting 20 genes of the cell cycle pathway were detected in 161 out of 255 patients (71.6%). Among them, 62 individuals exhibited >2 CNVs affecting the cell cycle pathway. Taking into account the number of individuals demonstrating CNV of these genes, a support for this hypothesis appears to be presented. Accordingly, we speculate that further studies of CNV burden across the genes implicated in related pathways might clarify whether zygotic genomic variation generates somatic mosaicism in health and disease.