Neurology gene panel

Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes...

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018-2023...

BACKGROUND: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18. AIM: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes...

Despite being immune cells of the central nervous system (CNS), microglia contribute to CNS development, maturation, and homeostasis, and microglia dysfunction has been implicated in several neurological disorders. Recent advancements in single-cell studies have uncovered unique microglia-specific gene expression. However, there is a need for a simple yet elegant multiplexed approach to quantifying microglia gene expression. To address this, we have designed a NanoString nCounter technology-based murine microglia-specific custom codeset comprising 178 genes...

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2)...

BACKGROUND: Peripheral neuropathies in mitochondrial disease are caused by mutations in nuclear genes encoding mitochondrial proteins, or in the mitochondrial genome. Whole exome or genome sequencing enable parallel testing of nuclear and mtDNA genes, and it has significantly advanced the genetic diagnosis of inherited diseases. Despite this, approximately 40% of all Charcot-Marie-Tooth (CMT) cases remain undiagnosed. METHODS: The genome-phenome analysis platform (GPAP) in RD-Connect was utilised to create a cohort of 2087 patients with at least one Human Phenotype Ontology (HPO) term suggestive of a peripheral neuropathy, from a total of 10,935 patients...

Whole-genome sequencing (WGS) has recently become the first-line genetic investigation for many suspected genetic neurological disorders. While its diagnostic capabilities are innumerable, as with any test, it has its limitations. Clinicians should be aware of where WGS is extremely reliable (detecting single-nucleotide variants), where its reliability is much improved (detecting copy number variants and small repeat expansions) and where it may miss/misinterpret a variant (large repeat expansions, balanced structural variants or low heteroplasmy mitochondrial DNA variants)...

OBJECTIVE: Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence-based recommendations for their integration into practice. METHODS: In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research-led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants...

A 35-year-old woman with a progressive, bilateral upper limb tremor, personality change, behavioral disturbance, and primary ovarian insufficiency was found to have AARS2 -related leukodystrophy. She had congenital nystagmus which evolved to head titubation by age 8 years and then developed an upper limb tremor in her mid-teens. These symptoms stabilized during her 20s, but soon after this presentation at age 35 years, neurologic and behavioral disturbances progressed rapidly over a 12-month period requiring transition to an assisted living facility with care support (4 visits/day) and assistance for all activities of daily living...

BACKGROUND: Congenital myopathies are a group of heterogeneous inherited disorders, mainly characterized by early-onset hypotonia and muscle weakness. The spectrum of clinical phenotype can be highly variable, going from very mild to severe presentations. The course also varies broadly resulting in a fatal outcome in the most severe cases but can either be benign or lead to an amelioration even in severe presentations. Muscle biopsy analysis is crucial for the identification of pathognomonic morphological features, such as core areas, nemaline bodies or rods, nuclear centralizations and congenital type 1 fibers disproportion...

Background: GNE myopathy (GM) is a rare autosomal recessive disorder caused by variants in the GNE gene and characterized by progressive distal muscle weakness and atrophy. We report a novel variant in the GNE gene causing GM in a consanguineous Malian family. Case presentation: A 19-year-old male patient from a consanguineous family of Bambara ethnicity was seen for progressive walking difficulty and frequent falls. Neurological examination found distalmuscle weakness and atrophy and reduced tendon reflexes in four limbs...

INTRODUCTION: Demyelination is one of the hallmarks of multiple sclerosis (MS). While remyelination occurs during the disease, it is incomplete from the start and strongly decreases with its progression, mainly due to the harm to oligodendrocyte progenitor cells (OPCs), causing irreversible neurological deficits and contributing to neurodegeneration. Therapeutic strategies promoting remyelination are still very preliminary and lacking within the current treatment panel for MS. METHODS: In a previous study, we identified 21 microRNAs dysregulated mostly in the CSF of relapsing and/or remitting MS patients...

PURPOSE: NLRP3-associated autoinflammatory disease (NLRP3-AID) is characterized by gain-of-function variants in the NLRP3 gene. Since there are little literature focusing on pediatric NLRP3-AID in China, we aimed to elucidate the phenotypic and genotypic profiles of Chinese patients with NLRP3-AID. METHODS: Patients with NLRP3-AID at three rheumatology centers in China were genotyped through whole exome sequencing or gene panel sequencing. Sanger sequencing was performed on all patients and their parents...

Charcot-Marie-Tooth disease (CMT) is one of the most common and genetically heterogeneous inherited neurological diseases, with more than 130 disease-causing genes. Whole genome sequencing (WGS) has improved diagnosis across genetic diseases, but the diagnostic impact in CMT is yet to be fully reported. We present the diagnostic results from a single specialist inherited neuropathy centre, including the impact of WGS diagnostic testing. Patients were assessed at our specialist inherited neuropathy centre from 2009-2023...

Ataxia telangiectasia (A-T) (OMIM 208900) is an autosomal recessive multisystem disorder characterised by progressive cerebellar ataxia, telangiectasias, immunodeficiency and a predisposition to malignancy. 'Variant' A-T has later onset of neurological symptoms and slower progression compared with the 'classic' form. A woman presented with short stature in late childhood. Karyotype revealed rearrangements involving chromosomes 7 and 14. A chromosomal breakage disorder gene panel demonstrated compound heterozygote mutations in her ATM gene including one mutation c...

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant genetic disorder of the small arteries that causes ischemic vascular events, subcortical dementia, behavioral changes, and migraine-like headaches. It is caused by a mutation in the NOTCH3 gene; this disease was first described in 1955 by van Bogaert. We present a 29-year-old woman who presented to the neurology department. She has no history of chronic degenerative diseases. She has been complaining of migraine-like headaches for the past six months...

Genetic testing has become a valuable diagnostic tool for movement disorders due to substantial advancements in understanding their genetic basis. However, the heterogeneity of movement disorders poses a significant challenge, with many genes implicated in different subtypes. This paper aims to provide a neurologist's perspective on approaching patients with hereditary hyperkinetic disorders with a focus on select forms of dystonia, paroxysmal dyskinesia, chorea, and ataxia. Age at onset, initial symptoms, and their severity, as well as the presence of any concurrent neurological and non-neurological features, contribute to the individual clinical profiles of hereditary non-parkinsonian movement disorders, aiding in the selection of appropriate genetic testing strategies...

INTRODUCTION: Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG18 is a rare, early-onset, complicated HSP, first reported as linked to biallelic ERLIN2 mutations. Recent cases of late-onset, pure HSP with monoallelic ERLIN2 variants prompt inquiries into the zygosity of such genetic conditions. The observed relationship between phenotype and mode of inheritance suggests a potential dominant negative effect of mutated ERLIN2 protein, potentially resulting in a milder phenotype...

The World Health Organization has updated their classification system for the diagnosis of gliomas, combining histological features with molecular data including isocitrate dehydrogenase 1 and codeletion of chromosomal arms 1p and 19q. 1p/19q codeletion analysis is commonly performed by fluorescence in situ hybridization (FISH). In this study, we developed a 57-gene targeted next-generation sequencing (NGS) panel including 1p/19q codeletion detection mainly to assess diagnosis and potential treatment response in melanoma, gastrointestinal stromal tumor, and glioma patients...

Dihydrolipoamide dehydrogenase (DLD) deficiency is a rare disease of genetic origin due to the malfunctioning of a shared subunit of three mitochondrial multi-enzyme complexes. Phenotypes of this disease are a set of clinical manifestations ranging from neonatal disorders to myopathy or recurrent episodes of liver failures, and vomiting for which no adequate or definitive treatment is currently available. This study described a case involving a 16-year-old boy who had experienced recurrent vomiting of unknown cause from age two...