WES-based screening of 7,000 newborns: A pilot study in Russia.

The effective implementation of whole-exome sequencing- and whole-genome sequencing-based diagnostics in the management of children affected with genetic diseases and the rapid decrease in the cost of next-generation sequencing (NGS) enables the expansion of this method to newborn genetic screening programs. Such NGS-based screening greatly increases the number of diseases that can be detected compared to conventional newborn screening, as the latter is aimed at early detection of a limited number of inborn diseases. Moreover, genetic testing provides new possibilities for family members of the proband, as many variants responsible for adult-onset conditions are inherited from the parents. However, the idea of NGS-based screening in healthy children raises issues of medical and ethical integrity as well as technical questions, including interpretation of the observed variants. Pilot studies have shown that both parents and medical professionals have moved forward and are enthused about these new possibilities. However, either the number of participants or the number of genes studied in previous investigations thus far has been limited to a few hundred, restricting the scope of potential findings. Our current study (NCT05325749) includes 7,000 apparently healthy infants born at our center between February 2021 and May 2023, who were screened for pathogenic variants in 2,350 genes. Clinically significant variants associated with early-onset diseases that can be treated, prevented, or where symptoms can be alleviated with timely introduced symptomatic therapy, were observed in 0.9% of phenotypically normal infants, 2.1% of the screened newborns were found to carry variants associated with reduced penetrance or monogenic diseases of adult-onset and/or variable expressivity, and 0.3% had chromosomal abnormalities. Here, we report our results and address questions regarding the interpretation of variants in newborns who were presumed to be healthy.

De novo start-loss variant in HIRA in patient with DiGeorge-like syndrome.

A case of a newborn with tetralogy of Fallot, corpus callosum hypoplasia, and phenotypic features similar to DiGeorge syndrome. Chromosomal microarray analysis did not reveal any alterations. Whole exome sequencing and Sanger sequencing identified a de novo variant in the HIRA gene resulting in the loss of the start codon.

Ultrafast vibrational control of organohalide perovskite optoelectronic devices using vibrationally promoted electronic resonance.

Vibrational control (VC) of photochemistry through the optical stimulation of structural dynamics is a nascent concept only recently demonstrated for model molecules in solution. Extending VC to state-of-the-art materials may lead to new applications and improved performance for optoelectronic devices. Metal halide perovskites are promising targets for VC due to their mechanical softness and the rich array of vibrational motions of both their inorganic and organic sublattices. Here, we demonstrate the ultrafast VC of FAPbBr3 perovskite solar cells via intramolecular vibrations of the formamidinium cation using spectroscopic techniques based on vibrationally promoted electronic resonance. The observed short (~300 fs) time window of VC highlights the fast dynamics of coupling between the cation and inorganic sublattice. First-principles modelling reveals that this coupling is mediated by hydrogen bonds that modulate both lead halide lattice and electronic states. Cation dynamics modulating this coupling may suppress non-radiative recombination in perovskites, leading to photovoltaics with reduced voltage losses.

Molecular diagnosis of tuberous sclerosis complex in fetuses and infants: an institutional case series.

OBJECTIVE: We describe the clinical and genetic characteristics of fetuses and infants diagnosed with tuberous sclerosis complex (TSC) in our centre, prenatally or neonatally, for a better understanding of the benefits of early screening. METHODS: In this retrospective study, we analysed the data on one fetus and nine infants with a definitive TSC diagnosis by genetic criteria (five patients carrying TSC1 variants and 5 patients carrying TSC2 variants). We explored the differences between phenotypes of patients carrying TSC1 and TSC2 pathogenic variants. RESULTS: The most common initial presenting features of TSC were cardiac rhabdomyomas (CRs) that were observed in nine out of ten patients. The most common postnatal features, besides CR, were presented with subependymal nodules-in five patients, and hypomelanotic macules-in four patients. In total, 10 variants causing TSC were detected in this study, including 5 novel variants. We demonstrated that patients with TSC2 variants had earlier onset and more severe clinical manifestations compared with patients carrying TSC1 variants. CONCLUSION: Early diagnosis of TSC improves genetic counselling and perinatal management.

De Novo Variant in the KCNJ9 Gene as a Possible Cause of Neonatal Seizures.

BACKGROUND: The reduction in next-generation sequencing (NGS) costs allows for using this method for newborn screening for monogenic diseases (MDs). In this report, we describe a clinical case of a newborn participating in the EXAMEN project (ClinicalTrials.gov Identifier: NCT05325749). METHODS: The child presented with convulsive syndrome on the third day of life. Generalized convulsive seizures were accompanied by electroencephalographic patterns corresponding to epileptiform activity. Proband WES expanded to trio sequencing was performed. RESULTS: A differential diagnosis was made between symptomatic (dysmetabolic, structural, infectious) neonatal seizures and benign neonatal seizures. There were no data in favor of the dysmetabolic, structural, or infectious nature of seizures. Molecular karyotyping and whole exome sequencing were not informative. Trio WES revealed a de novo variant in the KCNJ9 gene (1:160087612T > C, p.Phe326Ser, NM_004983), for which, according to the OMIM database, no association with the disease has been described to date. Three-dimensional modeling was used to predict the structure of the KCNJ9 protein using the known structure of its homologs. According to the predictions, Phe326Ser change possibly disrupts the hydrophobic contacts with the valine side chain. Destabilization of the neighboring structures may undermine the formation of GIRK2/GIRK3 tetramers necessary for their proper functioning. CONCLUSIONS: We believe that the identified variant may be the cause of the disease in this patient but further studies, including the search for other patients with the KCNJ9 variants, are needed.

Suppression of dynamic disorder by electrostatic interactions in structurally close organic semiconductors.

Dynamic disorder manifested in fluctuations of charge transfer integrals considerably hinders charge transport in high-mobility organic semiconductors. Accordingly, strategies for suppression of the dynamic disorder are highly desirable. In this study, we suggest a novel promising strategy for suppression of dynamic disorder-tuning the molecular electrostatic potential. Specifically, we show that the intensities of the low-frequency (LF) Raman spectra for crystalline organic semiconductors consisting of π-isoelectronic small molecules (i.e. bearing the same number of π electrons)-benzothieno[3,2-b][1]benzothiophene (BTBT), chrysene, tetrathienoacene (TTA) and naphtho[1,2-b:5,6-b']dithiophene (NDT)-differ significantly, indicating significant differences in the dynamic disorder. This difference is explained by suppression of the dynamic disorder in chrysene and NDT because of stronger intermolecular electrostatic interactions. As a result, guidelines for the increase of the crystal rigidity for the rational design of high-mobility organic semiconductors are suggested.

Toward probing of the local electron-phonon interaction in small-molecule organic semiconductors with Raman spectroscopy.

Electron-phonon interaction strongly affects and often limits charge transport in organic semiconductors (OSs). However, approaches to its experimental probing are still in their infancy. In this study, we probe the local electron-phonon interaction (quantified by the charge-transfer reorganization energy) in small-molecule OSs by means of Raman spectroscopy. Applying density functional theory calculations to four series of oligomeric OSs-polyenes, oligofurans, oligoacenes, and heteroacenes-we extend the previous evidence that the intense Raman vibrational modes considerably contribute to the reorganization energy in several molecules and molecular charge-transfer complexes, to a broader scope of OSs. The correlation between the contribution of the vibrational mode to the reorganization energy and its Raman intensity is especially prominent for the resonance conditions. The experimental Raman spectra obtained with various excitation wavelengths are in good agreement with the theoretical ones, indicating the reliability of our calculations. We also establish for the first time relations between the spectrally integrated Raman intensity, the reorganization energy, and the molecular polarizability for the resonance and off-resonance conditions. The results obtained are expected to facilitate the experimental studies of the electron-phonon interaction in OSs for an improved understanding of charge transport in these materials.

Fluorinated Thiophene-Phenylene Co-Oligomers for Optoelectronic Devices.

Organic optoelectronics requires materials combining bright luminescence and efficient ambipolar charge transport. Thiophene-phenylene co-oligomers (TPCOs) are promising highly emissive materials with decent charge-carrier mobility; however, they typically show poor electron injection in devices, which is usually assigned to high energies of their lowest unoccupied molecular orbitals (LUMOs). A widely used approach to lower the frontier orbitals energy levels of a conjugated molecule is its fluorination. In this study, we synthesized three new fluorinated derivatives of one of the most popular TPCOs, 2,2'-(1,4-phenylene)bis[5-phenylthiophene] (PTPTP) and studied them by cyclic voltammetry, absorption, photoluminescence, and Raman spectroscopies. The obtained data reveal a positive effect of fluorination on the optoelectronic properties of PTPTP: LUMO levels are finely tuned, and photoluminescence quantum yield and absorbance are increased. We then grew crystals from fluorinated PTPTPs, resolved their structures, and showed that fluorination dramatically affects the packing motif and facilitates π-stacking. Finally, we fabricated thin-film organic field-effect transistors (OFETs) and demonstrated a strong impact of fluorination on charge injection/transport for both types of charge carriers, namely, electrons and holes. Specifically, balanced ambipolar charge transport and electroluminescence were observed only in the OFET active channel based on the partially fluorinated PTPTP. The obtained results can be extended to other families of conjugated oligomers and highlight the efficiency of fluorination for rational design of organic semiconductors for optoelectronic devices.

Ground-State Geometry and Vibrations of Polyphenylenevinylene Oligomers.

Conformational space of polyphenylenevinylene oligomers is systematically investigated computationally at energies relevant for room temperature dynamics in a solvent and in a solid state. Our calculations show that optimal oligomer structures are essentially planar. However, lack of a deep minimum at the planar geometry allows for large molecular deformations even at very low temperatures. At larger angles, rotational motion of dihedrals intermix with two orthogonal bending motions of the entire molecule. In a crystalline environment these degrees of freedom intermix with translational and rotational motions, whereas purely intramolecular modes are well separated. The reliability of our calculations is confirmed by an excellent match of the theoretical and experimental Raman spectra of crystalline stilbene in the entire spectral range including the low-frequency part. Obtained results provide important insights into nature of low-frequency vibrations, which play a key role in charge transport in organic semiconductors.

Impact of terminal substituents on the electronic, vibrational and optical properties of thiophene-phenylene co-oligomers.

Owing to the combination of efficient charge transport and bright luminescence, thiophene-phenylene co-oligomers (TPCOs) are promising materials for organic light-emitting devices such as diodes, transistors and lasers. The synthetic flexibility of TPCOs enables facile tuning of their properties. In this study, we address the effect of various electron-donating and electron-withdrawing symmetric terminal substituents (fluorine, methyl, trifluoromethyl, methoxy, tert-butyl, and trimethylsilyl) on frontier orbitals, charge distribution, static polarizabilities, molecular vibrations, bandgaps and photoluminescence quantum yields of 5,5'-diphenyl-2,2'-bithiophene (PTTP). By combining DFT calculations with cyclic voltammetry and absorption, photoluminescence, and Raman spectroscopies, we show that symmetric terminal substitution tunes the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies of TPCOs within a range of ∼0.7 eV, shifts the frequencies of the vibrational modes associated with the phenyl rings, changes the photoluminescence quantum yield by about two-fold and slightly changes the bandgap by ∼0.1 eV. We demonstrate that these effects are governed by two factors: the Hammet constant of the substituents and their involvement in the π-conjugation/hyperconjugation described by the effective conjugation length of the substituted oligomer. A detailed picture underlying the effect of the terminal substituents on the electronic, vibrational and optical properties of TPCOs is presented. Overall, the unraveled relationships between the structure and the properties of the substituted PTTPs should facilitate a rational design of π-conjugated (co-)oligomers for efficient organic optoelectronic devices.