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.

Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.

AFG3L2 is a mitochondrial protease exerting protein quality control in the inner mitochondrial membrane. Heterozygous AFG3L2 mutations cause spinocerebellar ataxia type 28 (SCA28) or dominant optic atrophy type 12 (DOA12), while biallelic AFG3L2 mutations result in the rare and severe spastic ataxia type 5 (SPAX5). The clinical spectrum of SPAX5 includes childhood-onset cerebellar ataxia, spasticity, dystonia and myoclonic epilepsy.

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 ( ) while a small subset are caused by genomic deletions upstream of the gene.

Genomic Diagnoses for Ectopic Intracerebral Calcifications.

Background And Objectives: Ectopic intracerebral calcifications (EICs) in the basal ganglia, thalamus, cerebellum, or white matter are seen in a variety of disease states or may be found incidentally on brain imaging. The clinical significance and proportion of cases attributable to an underlying genetic cause is unknown.

Methods: This retrospective cohort study details the clinical, imaging, and genomic findings of 44 patients with EICs who had no established diagnosis despite extensive medical workup.

Germline loss-of-function variants are enriched in subjects with pituitary hypersecretion.

Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.

Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A.

TNF-Blockade for Primary Stroke Prevention in Adenosine Deaminase 2 Deficiency: A Case Series.

Objectives: Adenosine deaminase 2 deficiency (DADA2) is a genetic, neurologic, and systemic vasculitis syndrome, which can lead to recurrent strokes, typically lacunar. In the cohort of now 60 patients followed up at the NIH Clinical Center (NIH CC), no patient has had a stroke since starting tumor necrosis factor (TNF) blockade. We present a family with multiple affected children to highlight the importance of TNF blockade not just as secondary stroke prevention but also as primary stroke prevention in genetically affected but clinically asymptomatic patients.

MYH2-associated myopathy caused by a novel splice-site variant.

MYH2 encodes MyHCIIa, a myosin heavy chain found in fast type 2A fibers. Pathogenic variants in this gene have previously been implicated in dominant and recessive forms of myopathy. Three individuals reported here are part of a family in which four generations of individuals are affected by a slowly progressive, predominantly proximal myopathy in an autosomal dominant inheritance pattern.

Gene expression changes in Tay-Sachs disease begin early in fetal brain development.

Treatment of monogenic disorders has historically relied on symptomatic management with limited ability to target primary molecular deficits. However, recent advances in gene therapy and related technologies aim to correct these underlying deficiencies, raising the possibility of disease management or even prevention for diseases that can be treated pre-symptomatically. Tay-Sachs disease (TSD) would be one such candidate, however very little is known about the presymptomatic stage of TSD.

A de novo hexokinase 1 (HK1) variant presenting as Boucher-Neuhäuser syndrome.

Boucher-Neuhäuser syndrome (BNHS) is characterized by chorioretinal dystrophy, hypogonadotropic hypogonadism, and cerebellar dysfunction and atrophy. The disorder has been associated with biallelic pathogenic variants in the patatin-like phospholipase domain-containing protein 6 (PNPLA6) gene. We present an individual with a clinical diagnosis consistent with BNHS who lacked any PNPLA6 variants but on quartet family exome sequencing had a de novo variant in the hexokinase 1 (HK1) gene (NM_000188.