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.

Integrated cytogenetic and high-resolution array CGH analysis of genomic alterations associated with MYCN amplification.

Amplification of oncogenes and closely linked flanking genes is common in some types of cancer and can be associated with complex chromosome rearrangements and/or co-amplification of non-syntenic chromosomal regions. To better understand the etiology and structural complexity of focal MYCN amplicons in human neuronal cancer, we investigated the precise chromosomal locations of high copy number genomic regions in MYCN amplified cell lines. An integrated cytogenetic map of the MYCN amplicon was created using high-resolution array CGH, spectral karyotyping (SKY), multi-color banding (mBAND), and fluorescence in situ hybridization (FISH) in 4 human neuronal tumor cell lines. The evidence of complex intra- and inter-chromosomal events, providing clues concerning the nature of the genomic mechanisms that contributed to the process of MYCN amplification, was observed. The presence of multiple co-amplified syntenic or non-syntenic sequences in the MYCN amplicon is quite intriguing. MYCN is usually centrally located in the amplicon; however, the structure and complexity of the amplicons were highly variable. It is noteworthy that clusters of unstable repetitive regions characterized by CNV sequences were present throughout the regions encompassed by MYCN gene amplification, and these sequences could provide a mechanism to destabilize this region of the genome. Complex structural rearrangements involving genomic losses and gains in the 2p24 region lead to MYCN amplification and that these rearrangements can trigger amplification events.

Baroreflex sensitivity in children, adolescents, and young adults with essential and white-coat hypertension.

UNLABELLED: Hypertension, which is a common cardiovascular disease in adults, could originate in childhood. The aim of the study was to show differences in baroreflex sensitivity and short-term blood-pressure variability between healthy and hypertensive children, adolescents and young adults, and those with white-coat effect with respect to obesity. We examined 54 subjects (11-21 years) who had repeatedly high causal blood pressure. Basing on 24-hour blood pressure monitoring, the subjects were divided into groups: 24 subjects with hypertension (Hy) and 30 subjects with white-coat effect (WhC). Hy and WhC subjects were compared with age-matched healthy controls in a ratio of 1 : 2 for both groups: 48 controls for hypertensive subjects (CoHy) and 60 for subjects with white-coat effect (CoWhC). Totally, 162 subjects were studied. Systolic blood pressure (SBP) and inter-beat intervals (IBI) were recorded in all subjects for 5 min (Finapres, metronome controlled breathing at a frequency of 0.33 Hz). The power spectra of SBP and IBI were calculated. Indices of baroreflex sensitivity (BRS [ms/mmHg] and BRSf [mHz/mmHg]) were determined by the cross-spectral method. The SBP variability was determined as SBP spectral power in the range of 10-second rhythm (SBP (0.1Hz)). The body mass index (BMI) was significantly higher in both Hy and WhC compared with their controls (Hy vs. CoHy; WhC vs. CoWhC: 24.6 +/- 6.0 kg/m (2) vs. 20.4 +/- 2.8 kg/m (2), p < 0.001; 23.2 +/- 5.9 kg/m (2) vs. 20.3 +/- 2.6 kg/m (2), p < 0.05). BRS was significantly decreased in both groups (Hy vs. CoHy; WhC vs. CoWhC: 6.0 +/- 2.7 ms/mmHg vs. 9.5 +/- 3.9 ms/mmHg, p < 0.001; 7.2 +/- 3.1 ms/mmHg vs. 10.9 +/- 6.2 ms/mmHg, p < 0.01), and BRSf as well (Hy vs. CoHy; WhC vs. CoWhC: 10.8 +/- 4.6 mHz/mmHg vs. 16.2 +/- 6.1 mHz/mmHg, p < 0.001; 13.0 +/- 4.9 mHz/mmHg vs. 18.3 +/- 8.7 mHz/mmHg, p < 0.01). The decrease of baroreflex sensitivity was linked with the increase in the variability of SBP (0.1Hz), which was significant in hypertensives only (Hy vs. CoHy; WhC vs. CoWhC: 142 +/- 96 mmHg (2)/Hz vs. 94 +/- 83 mmHg (2)/Hz, p < 0.01; 121 +/- 131 mmHg (2)/Hz vs. 107 +/- 98 mmHg (2)/Hz). CONCLUSION: The mild increase of BMI was associated with white-coat effect and a BRS and BRSf decrease. The greater increase of BMI was associated with hypertension and a deeper BRS and BRSf decrease. This greater decrease of BRS and BRSf in hypertensives was linked with the increased SBP-variability.