Challenging Diagnosis of a Patient with Two Novel Variants in the Gene.

We report a case of -associated autosomal recessive spinocerebellar ataxia (SCAR8) presenting with a complex multisystemic phenotype, including highly elevated creatine kinase levels and lower-leg muscle atrophy. In addition to identifying two novel pathogenic variants in the gene, whole-exome sequencing revealed three variants of uncertain significance in the gene. Electromyography and muscle magnetic resonance imaging indicated a neurogenic pattern of muscle involvement.

Asymmetric scapuloperoneal phenotype of -related distal myopathy: case series.

Recent research has sparked a discussion on the spectrum of diseases linked to the gene associated with amyotrophic lateral sclerosis and distal myopathy with vocal cord and pharyngeal weakness (VCPDM). To date, fewer than 50 cases of VCPDM have been reported in the literature. We aim to build upon the work of previous researchers by gathering additional information about VCPDM.

High-throughput single-cell transcriptomics of bacteria using combinatorial barcoding.

Microbial split-pool ligation transcriptomics (microSPLiT) is a high-throughput single-cell RNA sequencing method for bacteria. With four combinatorial barcoding rounds, microSPLiT can profile transcriptional states in hundreds of thousands of Gram-negative and Gram-positive bacteria in a single experiment without specialized equipment. As bacterial samples are fixed and permeabilized before barcoding, they can be collected and stored ahead of time.

Expanding the Phenotype of Hereditary Congenital Facial Paresis Type 3.

The gene encodes a homeobox transcription factor pivotal in the development of rhombomere 4. Biallelic pathogenic variants in this gene are associated with congenital facial paresis type 3 (HCFP3). Only seven single nucleotide variants have been reported in the literature to date.

Pediatric Patients with Sitosterolemia: Next-Generation Sequencing and Biochemical Examination in Clinical Practice.

Here, we report the pediatric cases of sitosterolemia, a rare autosomal-recessive genetic disorder, characterized by high concentrations of plant sterols in blood and heterogeneity manifestations. All three patients (two girls aged 2 and 6 years old, and one boy aged 14 years old) were initially diagnosed with hypercholesterinemia. Next-generation sequencing (NGS) revealed homozygous (p.

[A case of spastic paraplegia with SPG4 and SPG3 associated mutations].

A rare case of autosomal dominant spastic paraplegia in a 36-year-old female with two reported earlier mutations of most common spastic paraplegia forms: SPG4 (mutation p.Cys28Leufs*20 in gene) and SPG3 (mutation p.Val405Met in gene) is presented.

How can systems approaches help us understand and treat infectious disease?

Leading researchers at the intersection of infectious disease and systems biology speak about how systems approaches have influenced modern infectious disease research and what these tools can offer for the future of the field.

Microbial single-cell RNA sequencing by split-pool barcoding.

Single-cell RNA sequencing (scRNA-seq) has become an essential tool for characterizing gene expression in eukaryotes, but current methods are incompatible with bacteria. Here, we introduce microSPLiT (microbial split-pool ligation transcriptomics), a high-throughput scRNA-seq method for Gram-negative and Gram-positive bacteria that can resolve heterogeneous transcriptional states. We applied microSPLiT to >25,000 cells sampled at different growth stages, creating an atlas of changes in metabolism and lifestyle.

De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features.

Intellectual disability is the most common developmental disorder caused by chromosomal aberrations as well as single-nucleotide variants (SNVs) and small insertions/deletions (indels). Here we report identification of a novel, probably pathogenic mutation in the WHSC1 gene in a patient case with phenotype overlapping the features of Wolf-Hirschhorn syndrome. Deletions involving WHSC1 (Wolf-Hirschhorn syndrome candidate 1 gene) were described earlier in patients with Wolf-Hirschhorn syndrome.

Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding.

To facilitate scalable profiling of single cells, we developed split-pool ligation-based transcriptome sequencing (SPLiT-seq), a single-cell RNA-seq (scRNA-seq) method that labels the cellular origin of RNA through combinatorial barcoding. SPLiT-seq is compatible with fixed cells or nuclei, allows efficient sample multiplexing, and requires no customized equipment. We used SPLiT-seq to analyze 156,049 single-nucleus transcriptomes from postnatal day 2 and 11 mouse brains and spinal cords.

Deep learning of the regulatory grammar of yeast 5' untranslated regions from 500,000 random sequences.

Our ability to predict protein expression from DNA sequence alone remains poor, reflecting our limited understanding of -regulatory grammar and hampering the design of engineered genes for synthetic biology applications. Here, we generate a model that predicts the protein expression of the 5' untranslated region (UTR) of mRNAs in the yeast We constructed a library of half a million 50-nucleotide-long random 5' UTRs and assayed their activity in a massively parallel growth selection experiment. The resulting data allow us to quantify the impact on protein expression of Kozak sequence composition, upstream open reading frames (uORFs), and secondary structure.

Slowdown of growth controls cellular differentiation.

How can changes in growth rate affect the regulatory networks behavior and the outcomes of cellular differentiation? We address this question by focusing on starvation response in sporulating Bacillus subtilis We show that the activity of sporulation master regulator Spo0A increases with decreasing cellular growth rate. Using a mathematical model of the phosphorelay-the network controlling Spo0A-we predict that this increase in Spo0A activity can be explained by the phosphorelay protein accumulation and lengthening of the period between chromosomal replication events caused by growth slowdown. As a result, only cells growing slower than a certain rate reach threshold Spo0A activity necessary for sporulation.

Chromosomal Arrangement of Phosphorelay Genes Couples Sporulation and DNA Replication.

Genes encoding proteins in a common regulatory network are frequently located close to one another on the chromosome to facilitate co-regulation or couple gene expression to growth rate. Contrasting with these observations, here, we demonstrate a functional role for the arrangement of Bacillus subtilis sporulation network genes on opposite sides of the chromosome. We show that the arrangement of two sporulation network genes, one located close to the origin and the other close to the terminus, leads to a transient gene dosage imbalance during chromosome replication.

Inverse Gillespie for inferring stochastic reaction mechanisms from intermittent samples.

Gillespie stochastic simulation is used extensively to investigate stochastic phenomena in many fields, ranging from chemistry to biology to ecology. The inverse problem, however, has remained largely unsolved: How to reconstruct the underlying reactions de novo from sparse observations. A key challenge is that often only aggregate concentrations, proportional to the population numbers, are observable intermittently.

Temporal competition between differentiation programs determines cell fate choice.

Multipotent differentiation, where cells adopt one of several possible fates, occurs in diverse systems ranging from bacteria to mammals. This decision-making process is driven by multiple differentiation programs that operate simultaneously in the cell. How these programs interact to govern cell fate choice is poorly understood.

Reversible and noisy progression towards a commitment point enables adaptable and reliable cellular decision-making.

Cells must make reliable decisions under fluctuating extracellular conditions, but also be flexible enough to adapt to such changes. How cells reconcile these seemingly contradictory requirements through the dynamics of cellular decision-making is poorly understood. To study this issue we quantitatively measured gene expression and protein localization in single cells of the model organism Bacillus subtilis during the progression to spore formation.