BK channel activity in skin fibroblasts from patients with neurological disorder.

Seventy-five unique variants in the gene have been identified from individuals with neurological disorders. However, variant pathogenicity and evidence for disease causality are lacking in most cases. In this study, the variants N999S and E656A (rs886039469 and rs149000684, respectively) were investigated from two individuals presenting with neurological disorders.

Neurodevelopmental Phenotyping and Genotyping in the Pediatric National Institute of Health Undiagnosed Disease Program.

The National Institute of Health (NIH) Undiagnosed Diseases Program (UDP) is an NIH project with the goal of providing both a comprehensive diagnosis and a better understanding of the many mechanisms of disease for patients with rare and undiagnosed conditions. Patients accepted to the program receive a careful review of their medical records and a tailored inpatient evaluation at the NIH Clinical Center in Bethesda, MD. For the pediatric population, systematic neurodevelopmental phenotypic evaluations are included.

Clinicopathological characterization of vacuolar tauopathy associated with VCP D395G.

Introduction: The clinical, radiological, and pathological features have not been well documented for the recently discovered autosomal-dominant vacuolar tauopathy (VT) harboring the Valosin-containing protein (VCP) p.Asp395Gly variant.

Methods: We investigated the clinical, neuropsychological, physiological, laboratory, and radiological data and neuropathological findings in five symptomatic VT cases who met the diagnostic criteria for frontotemporal dementia (FTD).

Systematic phenotype and genotype characterization of Moebius syndrome.

Purpose: To explore the phenotypic spectrum and genetic etiologies of Moebius Syndrome (MBS), a rare neurological disorder defined by congenital, nonprogressive facial weakness and limitations in ocular abduction.

Methods: We applied strict diagnostic criteria and conducted clinical phenotyping of 149 individuals with MBS. Subsequently, we performed exome and/or genome sequencing on 67 of these individuals and 117 unaffected family members.

Association of life's essential 8 score with incidence of atrial fibrillation: The Framingham heart study.

Background: Atrial fibrillation (AF) burden can be reduced by targeting modifiable risk factors. Limited data exist on the association between American Heart Association's Life's Essential 8 (LE8) score (higher scores healthier) and AF incidence.

Methods: We studied AF-free Framingham Heart Study Offspring and Omni 1 participants aged ≥45 years who attended ≥1 index exam in which LE8 components were assessed.

Organ Donation for Research Biobanking Among Historically Marginalized Racial and Ethnic Groups: A Systematic Review.

Importance: Research biobanks of human cells and tissues, particularly tissues accessible only after death, are crucial for advancing the understanding of human pathophysiological function. Research biobanks are bereft of tissues from individuals of diverse races and ethnicities, thus limiting the generalizability of biobank findings.

Objective: To evaluate the barriers and facilitators to participation in postmortem brain donation for research among individuals from historically marginalized races and ethnicities.

A genome-wide approach for the discovery of novel repeat expansion disorders in the Undiagnosed Diseases Network cohort.

Purpose: The Undiagnosed Diseases Network is a National Institutes of Health funded research study that aims to solve a broad clinical spectrum of challenging rare disease cases. Participants receive care from multiple clinical specialists, who collaborate to perform deep phenotyping and state-of-the-art multiomics analyses. As bioinformatics of short-read sequencing has matured, the discovery of repeat expansion disorders (REDs) is accelerating.

Deep Learning Cerebellar Magnetic Resonance Imaging Segmentation in Late-Onset GM2 Gangliosidosis: Implications for Phenotype.

Late-onset Tay-Sachs (LOTS) disease and late-onset Sandhoff disease (LOSD) have long been considered indistinguishable due to similar clinical presentations and shared biochemical deficits. However, recent magnetic resonance imaging (MRI) studies have shown distinct cerebellar atrophy associated with LOTS. In this study, we furthered this investigation to determine if the cerebellar atrophy is globally uniform or preferentially targets certain cerebellar regions.

Late-onset GM2 gangliosidosis: magnetic resonance imaging, diffusion tensor imaging, and correlational fiber tractography differentiate Tay-Sachs and Sandhoff diseases.

GM2 gangliosidosis is lysosomal storage disorder caused by deficiency of the heterodimeric enzyme β-hexosaminidase A. Tay-Sachs disease is caused by variants in HEXA encoding the α-subunit and Sandhoff disease is caused by variants in HEXB encoding the β-subunit. Due to shared clinical and biochemical findings, the two have been considered indistinguishable.

Heterozygous RAB3A variants cause cerebellar ataxia by a partial loss-of-function mechanism.

RAB3A encodes a small GTP-binding protein that is abundant in brain synaptic vesicles and crucial for the release of neurotransmitters and synaptic plasticity. Here, we identified RAB3A as a candidate gene for autosomal dominant cerebellar ataxia by two independent approaches: linkage in a large dominant ataxia family and, in parallel, an untargeted computational genetic association approach, analysing the 100 000 Genomes Project datasets. To validate the role of RAB3A in ataxia, we next screened large rare disease databases for rare heterozygous RAB3A variants in probands with ataxia features.

-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Heterozygous mutations in are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although -related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease.

Statin Use and Cardiovascular Risk in Young Adults in the United States.

Introduction: Atherosclerotic cardiovascular disease pathogenesis begins in early adulthood, yet guidance on statin use for primary prevention in young adults is limited.

Methods: This is a retrospective multicenter cohort study of adults aged 20-39 years receiving primary care within 87 U.S.

An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants.

The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene (LMNB1) while a small subset are caused by genomic deletions upstream of the gene.

Tay-Sachs and Sandhoff Diseases: Diffusion tensor imaging and correlational fiber tractography findings differentiate late-onset GM2 Gangliosidosis.

GM2 gangliosidosis is lysosomal storage disorder caused by deficiency of the heterodimeric enzyme β-hexosaminidase A. Tay-Sachs disease is caused by variants in encoding the α-subunit and Sandhoff disease is caused by variants in encoding the β-subunit. Due to shared clinical and biochemical findings, the two have been considered indistinguishable.

Chedíak-Higashi Syndrome: Hair-to-toe spectrum.

Chedíak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder caused by mutations in the Lysosomal Trafficking Regulator (LYST) gene, leading to defective lysosomal function in immune cells, melanocytes, and neurons. Clinically, CHS is characterized by a spectrum of symptoms, including immunodeficiency, partial oculocutaneous albinism, bleeding tendencies, neurodevelopmental deficits and progressive neurodegenerative symptoms. The severity of CHS correlates with the type of LYST mutation: the classic form, linked to nonsense or frameshift mutations, presents early in childhood with severe immune dysfunction, recurrent infections, and a high risk of hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory state.

An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.

Introduction: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization.

Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia.

Neuronal ceroid lipofuscinosis (NCL), type 6 (CLN6) is a neurodegenerative disorder associated with progressive neurodegeneration leading to dementia, seizures, and retinopathy. encodes a resident-ER protein involved in trafficking lysosomal proteins to the Golgi. CLN6p deficiency results in lysosomal dysfunction and deposition of storage material comprised of Nile Red lipids/proteolipids that include subunit C of the mitochondrial ATP synthase (SUBC).

LUSTR: a new customizable tool for calling genome-wide germline and somatic short tandem repeat variants.

Background: Short tandem repeats (STRs) are widely distributed across the human genome and are associated with numerous neurological disorders. However, the extent that STRs contribute to disease is likely under-estimated because of the challenges calling these variants in short read next generation sequencing data. Several computational tools have been developed for STR variant calling, but none fully address all of the complexities associated with this variant class.

Adult-onset neurodegeneration in XMEN disease.

Background: XMEN (X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV), and N-linked glycosylation defect) disease results from loss-of-function mutations in MAGT1, a protein that serves as a magnesium transporter and a subunit of the oligosaccharyltransferase (OST) complex. MAGT1 deficiency disrupts N-linked glycosylation, a critical regulator of immune function. XMEN results in recurrent EBV infections and a propensity for EBV-driven malignancies.

An P93S variant dysregulates TDP-43 and causes corticobasal syndrome.

As genetic testing has become more accessible and affordable, variants of uncertain significance (VUS) are increasingly identified, and determining whether these variants play causal roles in disease is a major challenge. The known disease-associated Annexin A11 (ANXA11) mutations result in ANXA11 aggregation, alterations in lysosomal-RNA granule co-trafficking, and TDP-43 mis-localization and present as amyotrophic lateral sclerosis or frontotemporal dementia. We identified a novel VUS in ANXA11 (P93S) in a kindred with corticobasal syndrome and unique radiographic features that segregated with disease.