The molecular consequences of FOXF1 missense mutations associated with alveolar capillary dysplasia with misalignment of pulmonary veins.

Background: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a fatal congenital lung disorder strongly associated with genomic alterations in the Forkhead box F1 (FOXF1) gene and its regulatory region. However, little is known about how FOXF1 genomic alterations cause ACD/MPV and what molecular mechanisms are affected by these mutations. Therefore, the effect of ACD/MPV patient-specific mutations in the FOXF1 gene on the molecular function of FOXF1 was studied.

LINE-1 retrotransposons contribute to mouse PV interneuron development.

Retrotransposons are mobile DNA sequences duplicated via transcription and reverse transcription of an RNA intermediate. Cis-regulatory elements encoded by retrotransposons can also promote the transcription of adjacent genes. Somatic LINE-1 (L1) retrotransposon insertions have been detected in mammalian neurons.

Epilepsy is an important feature of KBG syndrome associated with poorer developmental outcome.

Objective: The aim of this study was to describe the epilepsy phenotype in a large international cohort of patients with KBG syndrome and to study a possible genotype-phenotype correlation.

Methods: We collected data on patients with ANKRD11 variants by contacting University Medical Centers in the Netherlands, an international network of collaborating clinicians, and study groups who previously published about KBG syndrome. All patients with a likely pathogenic or pathogenic ANKRD11 variant were included in our patient cohort and categorized into an "epilepsy group" or "non-epilepsy group".

Fast and accurate protein structure search with Foldseek.

As structure prediction methods are generating millions of publicly available protein structures, searching these databases is becoming a bottleneck. Foldseek aligns the structure of a query protein against a database by describing tertiary amino acid interactions within proteins as sequences over a structural alphabet. Foldseek decreases computation times by four to five orders of magnitude with 86%, 88% and 133% of the sensitivities of Dali, TM-align and CE, respectively.

Insight into the content of and experiences with follow-up conversations with bereaved parents in paediatrics: A systematic review.

Aim: A follow-up conversation with bereaved parents is a relatively well-established intervention in paediatric clinical practice. Yet, the content and value of these conversations remain unclear. This review aims to provide insight into the content of follow-up conversations between bereaved parents and regular healthcare professionals (HCPs) in paediatrics and how parents and HCPs experience these conversations.

Structural mapping of GABRB3 variants reveals genotype-phenotype correlations.

Purpose: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations.

Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.

Modifier genes in SCN1A-related epilepsy syndromes.

Background: SCN1A is one of the most important epilepsy-related genes, with pathogenic variants leading to a range of phenotypes with varying disease severity. Different modifying factors have been hypothesized to influence SCN1A-related phenotypes. We investigate the presence of rare and more common variants in epilepsy-related genes as potential modifiers of SCN1A-related disease severity.

LINE-1 Evasion of Epigenetic Repression in Humans.

Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells.

Influence of common SCN1A promoter variants on the severity of SCN1A-related phenotypes.

Background: Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants.

Outcomes and comorbidities of SCN1A-related seizure disorders.

Purpose: Differentiating between Dravet syndrome and non-Dravet SCN1A-related phenotypes is important for prognosis regarding epilepsy severity, cognitive development, and comorbidities. When a child is diagnosed with genetic epilepsy with febrile seizures plus (GEFS+) or febrile seizures (FS), accurate prognostic information is essential as well, but detailed information on seizure course, seizure freedom, medication use, and comorbidities is lacking for this milder patient group. In this cross-sectional study, we explore disease characteristics in milder SCN1A-related phenotypes and the nature, occurrence, and relationships of SCN1A-related comorbidities in both patients with Dravet and non-Dravet syndromes.

Assessment of parental mosaicism in -related epilepsy by single-molecule molecular inversion probes and next-generation sequencing.

Background: Dravet syndrome is a severe genetic encephalopathy, caused by pathogenic variants in Low-grade parental mosaicism occurs in a substantial proportion of families (7%-13%) and has important implications for recurrence risks. However, parental mosaicism can remain undetected by methods regularly used in diagnostics. In this study, we use single-molecule molecular inversion probes (smMIP), a technique with high sensitivity for detecting low-grade mosaic variants and high cost-effectiveness, to investigate the incidence of parental mosaicism of variants in a cohort of 90 families and assess the feasibility of this technique.

IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences.

Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants.

Relationship of electrophysiological dysfunction and clinical severity in SCN2A-related epilepsies.

Variants in the SCN2A gene cause a broad spectrum of epilepsy syndromes of variable severity including benign neonatal-infantile epilepsy (BFNIE), developmental and epileptic encephalopathies (DEE), and other neuropsychiatric disorders. Here, we studied three newly identified variants, which caused distinct phenotypes observed in nine affected individuals of three families, including BFNIE, and DEE with intractable neonatal seizures. Whole cell patch-clamp recordings of transfected tsA201 cells disclosed an increased current density and an increased subthreshold sodium inward current upon an action potential stimulus (p.

RNase H2, mutated in Aicardi-Goutières syndrome, promotes LINE-1 retrotransposition.

Long INterspersed Element class 1 (LINE-1) elements are a type of abundant retrotransposons active in mammalian genomes. An average human genome contains ~100 retrotransposition-competent LINE-1s, whose activity is influenced by the combined action of cellular repressors and activators. TREX1, SAMHD1 and ADAR1 are known LINE-1 repressors and when mutated cause the autoinflammatory disorder Aicardi-Goutières syndrome (AGS).

L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution.

LINE-1 (L1) retrotransposons are a source of insertional mutagenesis in tumor cells. However, the clinical significance of L1 mobilization during tumorigenesis remains unclear. Here, we applied retrotransposon capture sequencing (RC-seq) to multiple single-cell clones isolated from five ovarian cancer cell lines and HeLa cells and detected endogenous L1 retrotransposition in vitro.

Azolla along a phosphorus gradient: biphasic growth response linked to diazotroph traits and phosphorus-induced iron chlorosis.

Azolla spp., a water fern often used for phytoremediation, is a strong phosphorus (P) accumulator due to its high growth rate and N fixing symbionts (diazotrophs). It is known that plant growth is stimulated by P, but the nature of the interactive response of both symbionts along a P gradient, and related changes in growth-limiting factors, are unclear.

Generation of a biotinylatable Sox2 mouse model to identify Sox2 complexes in vivo.

Sox2 is a Sry-box containing family member of related transcription factors sharing homology in their DNA binding domain. Sox2 is important during different stages of development, and previously we showed that Sox2 plays an important role in branching morphogenesis and epithelial cell differentiation in lung development. The transcriptional activity of Sox2 depends on its interaction with other proteins, leading to 'complex-specific' DNA binding and transcriptional regulation.

Plasma melatonin levels in hip fracture patients with and without delirium: A confirmation study.

Background: Melatonin plays a major role in maintaining circadian rhythm. Changes in melatonin metabolism might lead to circadian rhythm disturbances which are often observed in delirious patients.

Aim: To assess if high morning plasma melatonin concentrations were associated with delirium.

Male patients affected by mosaic PCDH19 mutations: five new cases.

Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature.