Novel variants in the NARS2 gene as a cause of infantile-onset severe epilepsy leading to fatal refractory status epilepticus: case study and literature review.

Biallelic variants in the NARS2 gene are the cause of a continuous spectrum of neurodegenerative disorders presenting with various severity-from spastic paraplegia, progressive neurodegeneration to Leigh and Alpers syndrome. Common clinical signs result from a mitochondrial dysfunction based on OXPHOS deficiency. Here, we present a patient with infantile-onset severe epilepsy leading to fatal refractory status epilepticus. Whole exome sequencing with Exomiser analysis based on HPO terms detected two novel NARS2 variants in a compound heterozygous state. To date, 18 different NARS2 disease-causing mutations have been described. Our study adds to the understanding of this mitochondrial disorder.

Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring.

Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.

Mechanism and genotype-phenotype correlation of two proximal 6q deletions characterized using mBAND, FISH, array CGH, and DNA sequencing.

Proximal 6q deletions have a milder phenotype than middle and distal 6q deletions. We describe 2 patients with non-overlapping deletions of about 15 and 19 Mb, respectively, which subdivide the proximal 6q region into 2 parts. The aberrations were identified using karyotyping and analysed using mBAND and array CGH. The unaffected mother of the first patient carried a mosaic karyotype with the deletion in all metaphases analysed and a small supernumerary marker formed by the deleted material in about 77% of cells. Her chromosome 6 centromeric signal was split between the deleted chromosome and the marker, suggesting that this deletion arose through the centromere fission mechanism. In this family the location of the proximal breakpoint in the centromere prevented cloning of the deletion junction, but the junction of the more distal deletion in the second patient was cloned and sequenced. This analysis showed that the latter aberration was most likely caused by non-homologous end joining. The second patient also had a remarkably more severe phenotype which could indicate a partial overlap of his deletion with the middle 6q interval. The phenotypes of both patients could be partly correlated with the gene content of their deletions and with phenotypes of other published patients.

Aggregation and other intermolecular interactions of biological buffers observed by capillary electrophoresis and UV photometry.

Electrophoretic and photometric experiments strongly indicate that monovalent anions, which arise by deprotonation of the nitrogen atom in zwitterionic Good's buffers 3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid (CAPSO) and 3-morpholinopropanesulfonic acid (MOPS), spontaneously aggregate. Cationic migration of sanguinarine (SA) and chelerythrine (CHE) in highly alkaline 1,3-bis[tris(hydroxymethyl)methylamino]propane (Bis-Tris-propane), in which the concentration of cations of both alkaloids is negligible, may be explained by the existence of an aggregate, which contains uncharged sanguinarine or chelerythrine and one monovalent cation of Bis-Tris-propane at least. Tendency of tris(hydroxymethyl)aminomethane (Tris), bis (2-hydroxyethyl)iminotris(hydroxymethyl)methane (Bis-Tris) and Bis-Tris-propane cations to ion pairing with synthetic cluster borane anions and with fused silica markedly rises up with the size and charge of these cations. The drop in mobility of cluster borane compounds sometimes exceeds 50% of their mobility found at identical pH and ionic strength in buffers with sodium cation. The electroosmosis drop approached 70% if background electrolyte contained Bis-Tris-propane cations instead of sodium cations. Nitrate, taken as a model inorganic ion, and four randomly chosen organic anions interacted markedly less with Tris, Bis-Tris and Bis-Tris-propane cations than cluster borane anions. 2-(N-morpholino)ethanesulfonic (MES) acid anions present in background electrolyte affect the ion pairing of Tris, Bis-Tris and Bis-Tris-propane cations with anionic analytes and, in this way influence also mobilites of these anionic analytes. Limited hydrophilicity at least one of interacting species appears to be the most probable cause of observed intermolecular interactions of biological buffers.