Mosaicism of a missense SCN1A mutation and Dravet syndrome in a Roma/Gypsy family.

SCN1A mutations account for a large proportion of Dravet syndrome patients, and are reported in other cases of epilepsy, such as some families with genetic epilepsy with febrile seizures plus (GEFS+). While most Dravet syndrome cases are caused by de novo mutations, 5% inherit a mutation from a mildly affected or symptom-free parent. Parental mosaicism has been identified, with documented cases involving truncating mutations or gene rearrangements. We describe a Roma/Gypsy family, where a missense mutation in SCN1A, p.D194N, is transmitted from a mosaic GEFS+ father to a child with Dravet syndrome. Mosaicism may be more common than assumed and should be considered regardless of the nature of the mutation.

Three novel SLC2A1 mutations in Bulgarian patients with different forms of genetic generalized epilepsy reflecting the clinical and genetic diversity of GLUT1-deficiency syndrome.

PURPOSE: GLUT1-deficiency syndrome (GLUT1-DS) is a metabolic brain disorder with a great clinical heterogeneity underlined by various mutations in the SLC2A1 gene which make the clinical and genetic diagnosis complicated. The purpose of our study is to investigate the genetic defects affecting the SLC2A1 gene in a group of Bulgarian patients with genetic generalized epilepsy (GGE), and to bring new insights into the molecular pathology of GLUT1-DS that would strengthen the genotype-phenotype correlations and improve the diagnostic procedure. METHODS: We have performed sequencing analysis of the SLC2A1 gene in thirty-eight Bulgarian patients with different forms of GGE having emerged in childhood followed by array comparative genome (aCGH) hybridization in patients with severe forms of GLUT1-DS who display extraneurological features. RESULTS: We have detected three novel SLC2A1 gene mutations that are predicted to have different impacts on the GLUT1 protein structure and function - one being to cause the amino acid substitution p.H160Q, another leading to the truncation p.Q360*, and also a 1p34.2 microdeletion. The overall frequency of the SLC2A1 mutations in the studied group is 8.1%. They have been found in clinical cases that differ notably by their severity. CONCLUSION: Our study enriches the mutation spectrum of the SLC2A1 gene by 3 novel cases that reflect the genetic and phenotypic diversity of GLUT1-DS and brings new insights into the molecular pathology of that disorder. The clinical data showed that the SLC2A1 genetic defects should be considered equally in the entire range of the clinical manifestations of GGE paying attention to the extraneurological features. The aCGH analysis should be considered as an ultimate step during the diagnostic procedure of GLUT1-DS in patients with a complex clinical picture of intractable epilepsy involving neuropsychological impairments and accompanied by extraneurological features.

Chromosomal microarray analysis of Bulgarian patients with epilepsy and intellectual disability.

High resolution chromosomal microarray analysis (CMA) has facilitated the identification of small chromosomal rearrangements throughout the genome, associated with various neurodevelopmental phenotypes, including ID/DD. Recently, it became evident that intellectual disability (ID)/developmental delay (DD) can occur with associated co-morbidities like epileptic seizures, autism and additional congenital anomalies. These observations require whole genome approach in order to detect the genetic causes of these complex disorders. In this study, we examined 92 patients of Bulgarian origin at age between 1 and 22 years with ID, generalized epilepsy, autistic signs and congenital anomalies. CMA was carried out using SurePrint G3 Human CGH Microarray Kit, 4 × 180 K and SurePrint G3 Unrestricted CGH ISCA v2, 4 × 180 K oligo platforms. Referral indications for selection of the patients were the presence of generalized refractory seizures disorders and co-morbid ID. Clearly pathogenic copy number variations (CNVs) were detected in eight patients (8.7%) from our cohort. Additionally, possibly pathogenic rearrangements of unclear clinical significance were detected in six individuals (6.5%), which make for an overall diagnostic yield of 15.2% among our cohort of patients. We report here the patients with clearly pathogenic CNVs, discuss the potential causality of the possibly pathogenic CNVs and make genotype - phenotype correlations. One novel possibly pathogenic heterozygous deletion in 15q22.31 region was detected in a case with ID/DD. Additionally, whole APBA2 gene duplication in 15q13.1 was found in three generations of a family with epilepsy, ID and psychiatric abnormalities. The results from this study allow us to define the genetic diagnosis in a subset of Bulgarian patients and improve the genetic counseling of the affected families. To our knowledge, this is the first aCGH evaluation of a Bulgarian cohort of children with epilepsy and ID so far.