A systematic framework for selecting gene-condition pairs for inclusion in newborn sequencing panels: Early Check implementation.

Purpose: Research is underway worldwide to investigate the feasibility, acceptability, and utility of sequencing-based newborn screening. Different methods have been used to select gene-condition pairs for screening, leading to highly inconsistent gene lists across studies.

Methods: Early Check developed and utilized actionability-based frameworks for evaluating gene-condition pairs for inclusion in newborn panels (panel 1-high actionability, panel 2-possible actionability).

Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals.

Purpose: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family.

Syndromic neurodevelopmental disorder associated with de novo variants in DDX23.

The DEAD/DEAH box RNA helicases are a superfamily of proteins involved in the processing and transportation of RNA within the cell. A growing literature supports this family of proteins as contributing to various types of human disorders from neurodevelopmental disorders to syndromes with multiple congenital anomalies. This article presents a cohort of nine unrelated individuals with de novo missense alterations in DDX23 (Dead-Box Helicase 23).

TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.

Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro.

Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism.

Chronic inflammation is a hallmark of obesity and is linked to the development of numerous diseases. The activation of toll-like receptor 4 (TLR4) by long-chain saturated fatty acids (lcSFAs) is an important process in understanding how obesity initiates inflammation. While experimental evidence supports an important role for TLR4 in obesity-induced inflammation in vivo, via a mechanism thought to involve direct binding to and activation of TLR4 by lcSFAs, several lines of evidence argue against lcSFAs being direct TLR4 agonists.

Sunburn, Thermal, and Chemical Injuries to the Skin.

Sunburn, thermal, and chemical injuries to the skin are common in the United States and worldwide. Initial management is determined by type and extent of injury with special care to early management of airway, breathing, and circulation. Fluid management has typically been guided by the Parkland formula, whereas some experts now question this.

Beyond Ohdo syndrome: A familial missense mutation broadens the MED12 spectrum.

Intellectual disability (ID) is estimated to affect 1-3% of the general population and is a common reason for referrals to pediatric and adult geneticists, as well as neurologists. There are many genetic and non-genetic causes of ID; X-linked forms are identifiable through their characteristic inheritance pattern. Current testing methods have been able to identify over 100 genes on the X chromosome responsible for X-linked intellectual disability (XLID) syndromes.

Military Health Care Dilemmas and Genetic Discrimination: A Family's Experience with Whole Exome Sequencing.

Whole-exome sequencing (WES) has increased our ability to analyze large parts of the human genome, bringing with it a plethora of ethical, legal, and social implications. A topic dominating discussion of WES is identification of "secondary findings" (SFs), defined as the identification of risk in an asymptomatic individual unrelated to the indication for the test. SFs can have considerable psychosocial impact on patients and families, and patients with an SF may have concerns regarding genomic privacy and genetic discrimination.

A 7-month-old male with Allan-Herndon-Dudley syndrome and the power of T3.

Allan-Herndon-Dudley syndrome (AHDS, MIM 300523) is an X-linked neurodegenerative disorder characterized by intellectual disability, severe hypotonia, diminished muscle mass, and progressive spastic paraplegia. All affected males have pathognomonic thyroid profiles with an elevated T3 , low-normal free T4 , and normal TSH. Mutations in the monocarboxylate transporter 8 (MCT8) gene, SLC16A2, have been found to be causative.

The dual-specificity phosphatase 2 (DUSP2) does not regulate obesity-associated inflammation or insulin resistance in mice.

Alterations in the immune cell profile and the induction of inflammation within adipose tissue are a hallmark of obesity in mice and humans. Dual-specificity phosphatase 2 (DUSP2) is widely expressed within the immune system and plays a key role promoting immune and inflammatory responses dependent on mitogen-activated protein kinase (MAPK) activity. We hypothesised that the absence of DUSP2 would protect mice against obesity-associated inflammation and insulin resistance.

In vitro palmitate treatment of myotubes from postmenopausal women leads to ceramide accumulation, inflammation and affected insulin signaling.

Menopause is associated with an increased incidence of insulin resistance and metabolic diseases. In a chronic palmitate treatment model, we investigated the role of skeletal muscle fatty acid exposure in relation to the metabolic deterioration observed with menopause. Human skeletal muscle satellite cells were isolated from premenopausal (n = 6) and postmenopausal (n = 5) women.

Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.

Pregnancy can precipitate thrombotic thrombocytopenic purpura (TTP). We present a prospective study of TTP cases from the United Kingdom Thrombotic Thrombocytopenic Purpura (UK TTP) Registry with clinical and laboratory data from the largest cohort of pregnancy-associated TTP and describe management through pregnancy, averting fetal loss and maternal complications. Thirty-five women presented with a first TTP episode during pregnancy: 23/47 with their first congenital TTP (cTTP) episode and 12/47 with acute acquired TTP in pregnancy.

Three clinical experiences with SNP array results consistent with parental incest: a narrative with lessons learned.

Single nucleotide polymorphism microarrays have the ability to reveal parental consanguinity which may or may not be known to healthcare providers. Consanguinity can have significant implications for the health of patients and for individual and family psychosocial well-being. These results often present ethical and legal dilemmas that can have important ramifications.

IκB kinase β (IKKβ) does not mediate feedback inhibition of the insulin signalling cascade.

In the present study, we have examined whether IKKβ [IκB (inhibitor of nuclear factor κB) kinase β] plays a role in feedback inhibition of the insulin signalling cascade. Insulin induces the phosphorylation of IKKβ, in vitro and in vivo, and this effect is dependent on intact signalling via PI3K (phosphoinositide 3-kinase), but not PKB (protein kinase B). To test the hypothesis that insulin activates IKKβ as a means of negative feedback, we employed a variety of experimental approaches.

Nucleotide usage, synonymous substitution pattern, and past recombination in genomes of Streptococcus pyogenes.

We examined (1) five variables summarizing nucleotide usage at synonymous sites; (2) pairwise patterns of nucleotide substitution among five genomes of Streptococcus pyogenes in order to examine the extent to which these variables are associated with past recombination events. Predicted prophage genes of MGAS10394 were characterized by an average pattern of nucleotide usage at synonymous sites that was distinct from that seen at most other genes. Ribosomal protein genes also showed a distinctive pattern, but one that differed from prophage genes in several key respects.