Publications by authors named "Chelsea Chambers"

12 Publications

  • Page 1 of 1

FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability.

Epilepsia 2021 01 6;62(1):e13-e21. Epub 2020 Dec 6.

Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia.

Chromosome 1q41-q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41-q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41-q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41-q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41-q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug-resistant epilepsy, and hyperkinetic movement disorders.
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http://dx.doi.org/10.1111/epi.16784DOI Listing
January 2021

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.

Hum Mutat 2020 01 26;41(1):299-315. Epub 2019 Oct 26.

Department of Dermatology and Venereology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
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http://dx.doi.org/10.1002/humu.23929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973139PMC
January 2020

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

Brain 2018 11;141(11):3160-3178

Neuropediatric Department, Centro Hospitalar do Porto, Porto, Portugal.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.
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http://dx.doi.org/10.1093/brain/awy263DOI Listing
November 2018

Phase determination using chromosomal microarray and fluorescence in situ hybridization in a patient with early onset Parkinson disease and two deletions in PRKN.

Mol Genet Genomic Med 2018 05 25;6(3):457-462. Epub 2018 Mar 25.

Department of Pathology, University of Virginia, Charlottesville, VA, USA.

Background: Mutations in the parkin gene (PRKN) are the most commonly identified genetic factors in early onset Parkinson disease (EOPD), with biallelic mutations, resulting in a clinical phenotype. However, normal variation is also common in PRKN, particularly in the form of copy number variation (CNV), challenging interpretation of genetic testing results. Here we report a case of a 29-year-old male with EOPD and two deletions in PRKN detected by chromosomal microarray (CMA).

Methods: The proband was clinically examined by a neurologist for postural instability with frequent falls, bradykinesia, gait freezing with festination, and hypophonia. Chromosomal microarray analysis (CMA) was performed on the proband and his parents using the Affymetrix CytoScan HD microarray. Subsequent fluorescence in situ hybridization (FISH) was performed on the proband and both parents.

Results: Chromosomal microarray detected the presence of two deletions of PRKN in the proband. Parental CMA analysis was performed to determine the clinical significance of this finding, as well as to demonstrate phase of these deletions. Parental CMA revealed that one deletion was paternally inherited and one deletion was de novo. A custom FISH approach was then successfully used to phase the deletions.

Conclusion: Chromosomal microarray and fluorescence in situ hybridization analysis of this trio identified two deletions in PRKN occurring in trans, providing a genetic etiology for the clinical diagnosis of EOPD. The determination of inheritance and phase of the deletions was critical to the proper interpretation of these results. These findings highlight the utility of CMA in the detection of clinically relevant CNVs in cases of EOPD, and also serve to emphasize the importance of follow-up FISH and parental testing.
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http://dx.doi.org/10.1002/mgg3.386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014474PMC
May 2018

A Case of KCNQ2-Associated Movement Disorder Triggered by Fever.

J Child Neurol 2017 Dec;32(14):1123-1124

2 Department of Neurology, University of Virginia, Charlottesville, VA, USA.

The differential diagnosis of fever-induced movement disorders in childhood is broad. Whole exome sequencing has yielded new insights into those cases with a suspected genetic basis. We report the case of an 8-year-old boy with a history of neonatal seizures who presented with near-continuous hyperkinetic movements of his limbs during a febrile illness. Initial diagnostic testing did not explain his abnormalities; however, given the suspicion for a channelopathy, whole exome sequencing was performed and it demonstrated a de novo pathogenic heterozygous variant in KCNQ2. There is an expanding phenotypic spectrum of heterozygous alterations in KCNQ2; however, this report provides the first description of a pathogenic KCNQ2 variant fever-induced hyperkinetic movement disorder in childhood. We also review the literature of cases previously published with the same pathogenic variant.
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http://dx.doi.org/10.1177/0883073817736702DOI Listing
December 2017

Autosomal recessive inheritance of -related generalized dystonia and myoclonus.

Neurol Genet 2017 Oct 25;3(5):193. Epub 2017 Sep 25.

Department of Neurology (M.J.B., C.C.), and Department of Pathology (E.S.W.), University of Virginia Health System, Charlottesville; and Department of Clinical Genomics and Neurology (R.D.), Mayo Clinic, Phoenix, AZ.

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http://dx.doi.org/10.1212/NXG.0000000000000193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612768PMC
October 2017

Clinical Reasoning: A 13-year-old boy with chronic ataxia and developmental delay.

Neurology 2017 03;88(13):e116-e121

From the Department of Neurology, University of Virginia, Charlottesville.

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http://dx.doi.org/10.1212/WNL.0000000000003768DOI Listing
March 2017

Axenfeld-Rieger Syndrome and Leukoencephalopathy Caused by a Mutation in FOXC1.

Pediatr Neurol 2017 Jan 9;66:113-114. Epub 2016 Sep 9.

Department of Neurology, University of Virginia, Charlottesville, Virginia; Department of Pediatrics, University of Virginia, Charlottesville, Virginia. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2016.08.020DOI Listing
January 2017

Clinical and Molecular Characterization of ALG1-CDG.

Pediatr Neurol Briefs 2016 Feb;30(2):14

Department of Neurology (Division of Pediatric Neurology), University of Virginia, Charlottesville, VA.

Investigators from the Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California and a large study group utilized a combination of exome sequencing, targeted gene panels, and Sanger sequencing to identify thirty-one pathogenic variants in thirty-nine affected individuals with ALG1-CDG from 32 families.
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http://dx.doi.org/10.15844/pedneurbriefs-30-2-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821836PMC
February 2016

Diagnostic NGS for Severe Neuromuscular Disorders.

Pediatr Neurol Briefs 2015 Nov;29(11):82

Division of Pediatric Neurology, Department of Neurology, University of Virginia, Charlottesville, VA.

Investigators from the University of Western Australia report the diagnostic yield of performing next generation sequencing (NGS; whole exome and targeted capture of 277 neuromuscular genes) in a heterogenous cohort of patients with neuromuscular disorders (NMD) presenting at or before birth.
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http://dx.doi.org/10.15844/pedneurbriefs-29-11-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747264PMC
November 2015

Review of Commercially Available Epilepsy Genetic Panels.

J Genet Couns 2016 Apr 5;25(2):213-7. Epub 2015 Nov 5.

Department of Neurology, University of Virginia, PO Box 800394, Charlottesville, VA, USA.

Next generation sequencing panels have revolutionized the diagnostic approach to patients with epilepsy. There are several commercial epilepsy panels available. We assessed the list of genes tested and consent forms for epilepsy panels available at seven laboratories. The panels varied in the number of genes included (70-465 genes). In some panels, genes not currently associated with epilepsy were included (up to 4 % of panel content). The panels also included genes for lysosomal storage disorders (6-12 %), congenital disorders of glycosylation (0-8.5 %), metabolic disorders (3.5-34 %), neurological syndromes (18-43 %) and multisystemic genetic syndromes (6.4-21 %). Informed consents differed significantly between laboratories ranging from basic information about genetic testing and possible results to information about insurance, genetic counseling and familial testing, and incidental findings.Our findings suggest that it is important to consider the range of genes offered on epilepsy panels and their predicted phenotypes in an effort toward improving the informed consent process.
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http://dx.doi.org/10.1007/s10897-015-9906-9DOI Listing
April 2016

Cognitive and affective outcomes of more severe compared to less severe carbon monoxide poisoning.

Brain Inj 2008 May;22(5):387-95

Psychology Department, Brigham Young University, Provo, Utah, USA.

Primary Objective: To assess cognitive sequelae, depression and anxiety following carbon monoxide (CO) poisoning.

Research Design: Prospective cohort study.

Methods And Procedures: This study prospectively followed 256 patients, 55 with less severe and 201 with more severe CO-poisoning. The prevalence of cognitive sequelae, depression and anxiety at 6 weeks, 6 months and 12 months was compared in patients with less severe and more severe CO-poisoning.

Main Outcomes And Results: Of the less severe CO-poisoned patients, 39% had cognitive sequelae, 21% depression and 30% anxiety at 6 weeks. Of the more severe CO-poisoned patients, 35% had cognitive sequelae, 16% depression and 11% anxiety at 6 weeks. There was no difference in the prevalence of cognitive sequelae at any time. The prevalence of depression was higher in patients with less compared with more severe CO-poisoning at 6 months (p = 0.04), but not 6 weeks or 12 months. The prevalence of anxiety was higher in patients with less compared to more severe CO-poisoning at 6 weeks (p = 0.008), but not 6 or 12 months. Anxiety decreased over time in the less severe group (p < 0.01).

Conclusion: CO-related cognitive sequelae, depression and anxiety are common and may be independent of poisoning severity.
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http://dx.doi.org/10.1080/02699050802008075DOI Listing
May 2008
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