Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital myopathy.

Dystonin (DST) encodes three major isoforms, DST-a, DST-b, and DST-e. Biallelic pathogenic variants in DST have previously been associated with two allelic monogenic disorders: Hereditary Sensory and Autonomic Neuropathy type VI (caused by a loss of DST-a) and Epidermolysis bullosa simplex 3 (caused by a loss of DST-e). We investigated patients diagnosed with congenital myopathy using exome or genome sequencing.

Pleiotropic effects of MORC2 derive from its epigenetic signature.

Heterozygous missense mutations in MORC2 have been implicated in various clinical entities, ranging from early-onset neurodevelopmental disorders to late-onset neuropathies. The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive. Here, we analyzed blood and fibroblast DNA methylation, transcriptomes, proteomes, and phenotypes of 53 MORC2 patients.

Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia.

Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated. To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families.

SIRT6-dependent functional switch via K494 modifications of RE-1 silencing transcription factor.

RE-1 silencing transcription factor (REST) is a key repressor of neural genes. REST is upregulated under stress signals, aging and neurodegenerative diseases, but although it is upregulated, its function is lost in Alzheimer's Disease. However, why it becomes inactive remains unclear.

Multi-omics in MECP2 duplication syndrome patients and carriers.

MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by the gain of dose of at least the genes MECP2 and IRAK1 and is characterised by intellectual disability (ID), developmental delay, hypotonia, epilepsy and recurrent infections. It mainly affects males, and females can be affected or asymptomatic carriers. Rett syndrome (RTT) is mainly triggered by loss of function mutations in MECP2 and is a well described syndrome that presents ID, epilepsy, lack of purposeful hand use and impaired speech, among others.

Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy.

Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous.

Identification of molecular signatures and pathways involved in Rett syndrome using a multi-omics approach.

Background: Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). MeCP2 is a multi-functional protein involved in many cellular processes, but the mechanisms by which its dysfunction causes disease are not fully understood. The duplication of the MECP2 gene causes a distinct disorder called MECP2 duplication syndrome (MDS), highlighting the importance of tightly regulating its dosage for proper cellular function.

Integrative omics approaches to advance rare disease diagnostics.

Over the past decade high-throughput DNA sequencing approaches, namely whole exome and whole genome sequencing became a standard procedure in Mendelian disease diagnostics. Implementation of these technologies greatly facilitated diagnostics and shifted the analysis paradigm from variant identification to prioritisation and evaluation. The diagnostic rates vary widely depending on the cohort size, heterogeneity and disease and range from around 30% to 50% leaving the majority of patients undiagnosed.

SIRT6 is a key regulator of mitochondrial function in the brain.

The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain.

Heterozygous BRCA1 and BRCA2 and Mismatch Repair Gene Pathogenic Variants in Children and Adolescents With Cancer.

Background: Genetic predisposition is has been identified as a cause of cancer, yet little is known about the role of adult cancer predisposition syndromes in childhood cancer. We examined the extent to which heterozygous pathogenic germline variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, MSH2, MSH6, MLH1, and PMS2 contribute to cancer risk in children and adolescents.

Methods: We conducted a meta-analysis of 11 studies that incorporated comprehensive germline testing for children and adolescents with cancer.

Guidelines for clinical interpretation of variant pathogenicity using RNA phenotypes.

Over the last 5 years, RNA sequencing (RNA-seq) has been established and is increasingly applied as an effective approach complementary to DNA sequencing in molecular diagnostics. Currently, three RNA phenotypes, aberrant expression, aberrant splicing, and allelic imbalance, are considered to provide information about pathogenic variants. By providing a high-throughput, transcriptome-wide functional readout on variants causing aberrant RNA phenotypes, RNA-seq has increased diagnostic rates by about 15% over whole-exome sequencing.

Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes.

Objective: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases.

The Hitchhiker's Guide to Untargeted Lipidomics Analysis: Practical Guidelines.

Lipidomics is a newly emerged discipline involving the identification and quantification of thousands of lipids. As a part of the omics field, lipidomics has shown rapid growth both in the number of studies and in the size of lipidome datasets, thus, requiring specific and efficient data analysis approaches. This paper aims to provide guidelines for analyzing and interpreting lipidome data obtained using untargeted methods that rely on liquid chromatography coupled with mass spectrometry (LC-MS) to detect and measure the intensities of lipid compounds.

Correction: Genetic algorithm-based personalized models of human cardiac action potential.

[This corrects the article DOI: 10.1371/journal.pone.

Genetic algorithm-based personalized models of human cardiac action potential.

We present a novel modification of genetic algorithm (GA) which determines personalized parameters of cardiomyocyte electrophysiology model based on set of experimental human action potential (AP) recorded at different heart rates. In order to find the steady state solution, the optimized algorithm performs simultaneous search in the parametric and slow variables spaces. We demonstrate that several GA modifications are required for effective convergence.

Spin noise explores local magnetic fields in a semiconductor.

Rapid development of spin noise spectroscopy of the last decade has led to a number of remarkable achievements in the fields of both magnetic resonance and optical spectroscopy. In this report, we demonstrate a new - magnetometric - potential of the spin noise spectroscopy and use it to study magnetic fields acting upon electron spin-system of an n-GaAs layer in a high-Q microcavity probed by elliptically polarized light. Along with the external magnetic field, applied to the sample, the spin noise spectrum revealed the Overhauser field created by optically oriented nuclei and an additional, previously unobserved, field arising in the presence of circularly polarized light.