Detection of submicroscopic chromosomal abnormalities using microarray analysis:The value and pitfalls in prenatal and postnatal diagnosis

Chromosomal microarray enables identifying small genomic deletions and duplications that are not routinely seen on karyotyping. Microarray analysis therefore has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children in the Netherlands since 2008. When invasive prenatal diagnosis is indicated, because of ultrasound abnormalities and/or an increased risk for common aneuploidies (trisomy 21, 18 or 13) at first trimester screening, microarray analysis instead of conventional karyotyping will be applied when targeted molecular rapid aneuploidy detection reveals no abnormalities. Microarray analysis provides around 12-15% extra diagnosis in cases of mental retardation and/or structural abnormalities and it can provide 6% extra diagnosis in prenatal samples with a normal karyotype. Besides finding evident causative abnormalities, microarray analysis increases the detection rates of VOUS (variants of unknown significance) that, in particular during a pregnancy, induce emotional burden en counselling difficulties. Furthermore, CNVs that are pathogenic but not related with the phenotype (e.g. deletion of an oncogene) may complicate pretest and posttest counselling as well, since these findings may have health consequences for both patient and family members. Clinicians who request microarray analysis should be aware of these implications. In this paper, two prenatal and four postnatal case reports illustrate the ability to identify more clinically relevant abnormalities, but also limitations and coincidental findings in microarray analysis.</p

Synthetic approaches to artificial photosynthesis: general discussion

Metals in Catalysis, Biomimetics & Inorganic Material

Optical excitations of defects in realistic nanoscale silica clusters: comparing the performance of density functional theory using hybrid functionals with correlated wavefunction methods

Optical excitations of low energy silica SiO24 clusters obtained by global optimization, as opposed to constructed by hand, are studied using a range of theoretical methods. By focusing on the lowest energy silica clusters we hope to capture at least some of the characteristic ways by which the dry surfaces of silica nanosystems preferentially terminate. Employing the six lowest energy SiO24 cluster isomers, we show that they exhibit a surprisingly wide range of geometries, defects, and associated optical excitations. Some of the clusters show excitations localized on isolated defects, which are known from previous studies using hydrogen-terminated versions of the defect in question. Other clusters, however, exhibit novel charge-transfer excitations in which an electron transfers between two spatially separated defects. In these cases, because of the inherent proximity of the constituent defects due to the small cluster dimensions, the excitation spectrum is found to be very different from that of the same defects in isolation. Excitation spectra of all clusters were calculated using time-dependent density functional theory TD-DFT and delta-SCF DFT DFT methods employing two different hybrid density functionals B3LYP and BB1K differing essentially in the amount of incorporated Hartree-Fock-like exchange HFLE. In all cases the results were compared with CASPT2 calculated values which are taken as a benchmark standard. In line with previous work, the spatially localized excitations are found to be well described by TD-DFT/B3LYP but which gives excitation energies that are significantly underestimated in the case of the charge-transfer excitations. The TD-DFT/BB1K combination in contrast is found to give generally good excitation energies for the lowest excited states of both localized and charge-transfer excitations. Finally, our calculations suggest that the increased quality of the predicted excitation spectra by adding larger amounts of HFLE is mainly due to an increased localization of the excited state associated with the elimination of spurious self-interaction inherent to semi-local DFT functionals

The effect of local environment on photoluminescence: a TD-DFT study of silanone groups on the surface of silica nanostructures

The optical absorption spectrum and lowest photoluminescence PL signal for silanone terminated silica nanostructures are studied using time-dependent density functional theory calculations on a range of realistic low energy silica nanocluster models. We show that the broad experimental absorption spectrum for silanone centers V. A. Radtsig and I. M. Senchenya Russ. Chem. Bull. 45, 1849 1996 is most likely the result of a synergetic combination of inhomogeneous broadening, thermal broadening and the small energy differences between different excitations. We further demonstrate that upon relaxation of the excited state the excited electron and hole localize on only one silanone center, and that there is a clear and distinct link between the local environment of a silanone center and its absorption and PL spectra. Finally, we provide strong evidence that the silanone center does not have a double bond between the constituent silicon and oxygen atoms but rather can be probably more aptly described as the =Si+-O− charge-transfer species

The fate of optical excitations in small polyhedral ZnS clusters: a theoretical study of the excitation and localization of electrons in Zn4S4 and Zn6S6

We explore the excited state energy landscape of small polyhedral zinc sulfide clusters (Zn4S4 and Zn6S6) using time-dependent density functional theory and correlated wave function based meth- ods. We predict the optical absorption and photoluminescence spectra of the polyhedral clusters and demonstrate that, upon relaxation of the excited state, these nanostructures break symmetry and an electron and a hole localize on a small number of Zn (electron) and S (hole) centers. We further test several exchange-correlation potentials for their ability to recover the correlated wave function description of the excited state. Finally, we discuss how the degeneracy of excited states in nanostruc- tures, such as those considered here, results in a Jahn-Teller distortion of the excited state geometry, and how numerical problems arising from this can be circumvented by starting the optimization of excited states from structures distorted along the ground state vibrational normal modes

Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development.

The regulated proliferation and differentiation of neural stem cells before the generation and migration of neurons in the cerebral cortex are central aspects of mammalian development. Periventricular neuronal heterotopia, a specific form of mislocalization of cortical neurons, can arise from neuronal progenitors that fail to negotiate aspects of these developmental processes. Here we show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia. Reducing the expression of Dchs1 or Fat4 within mouse embryonic neuroepithelium increased progenitor cell numbers and reduced their differentiation into neurons, resulting in the heterotopic accumulation of cells below the neuronal layers in the neocortex, reminiscent of the human phenotype. These effects were countered by concurrent knockdown of Yap, a transcriptional effector of the Hippo signaling pathway. These findings implicate Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis

Partial loss of USP9X function leads to a male neurodevelopmental and behavioral disorder converging on transforming growth factor β signaling

Background: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. Methods: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. Results: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. Conclusions: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocannpal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.Genetics of disease, diagnosis and treatmen