BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations.

An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.

A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing.

OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein-protein interactions and regulates a stem cell splicing program.

Early rhombic lip Protogenin stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

We identify a population of Protogenin-positive (PRTG) MYC NESTIN stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL). Oncogenic transformation of early Prtg rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG stem cells grow adjacent to a human-specific interposed vascular plexus in the RL, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma.

Known pathogenic gene variants and new candidates detected in sudden unexpected infant death using whole genome sequencing.

The purpose of this study is to gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID). Whole Genome Sequencing (WGS) was performed on 144 infants that succumbed to SUID, and 573 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences.

Chronic intermittent hypoxia elicits distinct transcriptomic responses among neurons and oligodendrocytes within the brainstem of mice.

Chronic intermittent hypoxia (CIH) is a prevalent condition characterized by recurrent episodes of oxygen deprivation, linked to respiratory and neurological disorders. Prolonged CIH is known to have adverse effects, including endothelial dysfunction, chronic inflammation, oxidative stress, and impaired neuronal function. These factors can contribute to serious comorbidities, including metabolic disorders and cardiovascular diseases.

Known pathogenic gene variants and new candidates detected in Sudden Unexpected Infant Death using Whole Genome Sequencing.

Purpose: To gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID).

Methods: Whole Genome Sequencing (WGS) was performed on 145 infants that succumbed to SUID, and 576 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences.

Dandy-Walker Phenotype with Brainstem Involvement: 2 Distinct Subgroups with Different Prognosis.

Background And Purpose: Although cardinal imaging features for the diagnostic criteria of the Dandy-Walker phenotype have been recently defined, there is a large range of unreported malformations among these patients. The brainstem, in particular, deserves careful attention because malformations in this region have potentially important implications for clinical outcomes. In this article, we offer detailed information on the association of brainstem dysgenesis in a large, multicentric cohort of patients with the Dandy-Walker phenotype, defining different subtypes of involvement and their potential clinical impact.

Macrocephaly and developmental delay caused by missense variants in RAB5C.

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C.

Structure, Function, and Genetics of the Cerebellum in Autism.

Autism spectrum disorders are common neurodevelopmental disorders that are defined by core behavioral symptoms but have diverse genetic and environmental risk factors. Despite its etiological heterogeneity, several unifying theories of autism have been proposed, including a central role for cerebellar dysfunction. The cerebellum follows a protracted course of development that culminates in an exquisitely crafted brain structure containing over half of the neurons in the entire brain densely packed into a highly organized structure.

Refining the Neuroimaging Definition of the Dandy-Walker Phenotype.

Background And Purpose: The traditionally described Dandy-Walker malformation comprises a range of cerebellar and posterior fossa abnormalities with variable clinical severity. We aimed to establish updated imaging criteria for Dandy-Walker malformation on the basis of cerebellar development.

Materials And Methods: In this multicenter study, retrospective MR imaging examinations from fetuses and children previously diagnosed with Dandy-Walker malformation or vermian hypoplasia were re-evaluated, using the choroid plexus/tela choroidea location and the fastigial recess shape to differentiate Dandy-Walker malformation from vermian hypoplasia.

Unified rhombic lip origins of group 3 and group 4 medulloblastoma.

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins. However, the anatomical and cellular complexity of developing human tissues-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice.

Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.

Purpose: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10.

Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development.

Medulloblastoma is currently subclassified into distinct DNA methylation subgroups/subtypes with particular clinico-molecular features. Using RNA sequencing (RNA-seq) in large, well-annotated cohorts of medulloblastoma, we show that transcriptionally group 3 and group 4 medulloblastomas exist as intermediates on a bipolar continuum between archetypal group 3 and group 4 entities. Continuum position is prognostic, reflecting a propensity for specific DNA copy-number changes, and specific switches in isoform/enhancer usage and RNA editing.

Human Cerebellar Development and Transcriptomics: Implications for Neurodevelopmental Disorders.

Developmental abnormalities of the cerebellum are among the most recognized structural brain malformations in human prenatal imaging. Yet reliable information regarding their cause in humans is sparse, and few outcome studies are available to inform prognosis. We know very little about human cerebellar development, in stark contrast to the wealth of knowledge from decades of research on cerebellar developmental biology of model organisms, especially mice.

-Related Dysgyria: An Under-Recognized Malformation of Cortical Development.

Background And Purpose: Pathogenic variants in the gene cause a distinctive arterial phenotype that has recently been described to be associated with brain malformation. Our objective was to further characterize gyral abnormalities in patients with pathogenic variants as per the 2020 consensus recommendations for the definition and classification of malformations of cortical development.

Materials And Methods: We performed a retrospective, multicentric review of patients with proved pathogenic variants, searching for the presence of malformations of cortical development.

The Influence of Chronic Pain and Catastrophizing on Patient Outcomes in an Athletic Therapy Setting.

Context: Chronic pain is a challenge for Athletic Trainers and Athletic Therapists working in a clinical or university setting. The fear avoidance model, including catastrophizing, is well established in other health professions but is not established in Athletic Training and Athletic Therapy and may affect rehabilitation outcomes.

Objective: To measure the influence of catastrophizing on rehabilitation outcomes of patients being treated in an Athletic Therapy setting.

NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain.

The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.

Strong yet incomplete reproductive isolation in is not contradicted by other lines of evidence: A reply to Toews et al.

Toews et al. assert that strong reproductive isolation in is inconsistent with other lines of evidence. Here, we discuss how strong yet incomplete reproductive isolation is consistent with other results from this system.

Evidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformation.

Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses.

Spatial and cell type transcriptional landscape of human cerebellar development.

The human neonatal cerebellum is one-fourth of its adult size yet contains the blueprint required to integrate environmental cues with developing motor, cognitive and emotional skills into adulthood. Although mature cerebellar neuroanatomy is well studied, understanding of its developmental origins is limited. In this study, we systematically mapped the molecular, cellular and spatial composition of human fetal cerebellum by combining laser capture microscopy and SPLiT-seq single-nucleus transcriptomics.