Papers by Christel Depienne
Medizinische Genetik
Noncoding repeat expansions are a well-known cause of genetic disorders mainly affecting the cent... more Noncoding repeat expansions are a well-known cause of genetic disorders mainly affecting the central nervous system. Missed by most standard technologies used in routine diagnosis, pathogenic noncoding repeat expansions have to be searched for using specific techniques such as repeat-primed PCR or specific bioinformatics tools applied to genome data, such as ExpansionHunter. In this review, we focus on GC-rich repeat expansions, which represent at least one third of all noncoding repeat expansions described so far. GC-rich expansions are mainly located in regulatory regions (promoter, 5′ untranslated region, first intron) of genes and can lead to either a toxic gain-of-function mediated by RNA toxicity and/or repeat-associated non-AUG (RAN) translation, or a loss-of-function of the associated gene, depending on their size and their methylation status. We herein review the clinical and molecular characteristics of disorders associated with these difficult-to-detect expansions.
Medizinische Genetik
Familial adult myoclonic epilepsy (FAME) is a rare autosomal dominant disorder characterized by m... more Familial adult myoclonic epilepsy (FAME) is a rare autosomal dominant disorder characterized by myoclonus and seizures. The genetic variant underlying FAME is an intronic repeat expansion composed of two different pentamers: an expanded TTTTA, which is the motif originally present at the locus, and an insertion of TTTCA repeats, which is usually located at the 3′ end and likely corresponds to the pathogenic part of the expansion. This repeat expansion has been identified so far in six genes located on different chromosomes, which remarkably encode proteins with distinct cellular localizations and functions. Although the exact pathophysiological mechanisms remain to be clarified, it is likely that FAME repeat expansions lead to disease independently of the gene where they occur. We herein review the clinical and molecular characteristics of this singular genetic disorder, which interestingly shares clinical features with other more common neurological disorders whose etiology remains...
Two of the most familiar method of voting is through voting polls and online voting. The main pro... more Two of the most familiar method of voting is through voting polls and online voting. The main problem with conventional method is the insecurity of the votes to be untemper. Another problem of voting methods is the existence of fraud in voting system. This paper is to propose a method in overcoming these flaws and problems by using the Blockchain technology. Blockchain technology is a secured database and has very high security. The technical concept of the Blockchain technology has many advantages and benefits that could be applied to many technical sectors and have the possibility in changing the world. The concept for this project is to develop a cryptocurrency implementation in the voting system. From there, the transaction votes are kept in the blockchain could be illustrated by examining the block hashes. The outcome of the project shows a transaction of coins from one voter's wallet into two candidates' wallet. The transactions were approved through a process of mining and the transactions of coins were a success. The data of the transactions were kept in the blockchain where unique blockhash, which acted as the block's fingerprint were generated. From there, the integrity of the blockchain technology is illustrated.
Cells
Background: Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants... more Background: Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants in SLC18A3 impairing the synthesis and recycling of acetylcholine (ACh) have recently been described. SLC18A3 encodes the vesicular ACh transporter (VAChT), modulating the active transport of ACh at the neuromuscular junction, and homozygous loss of VAChT leads to lethality. Methods: Exome sequencing (ES) was carried out to identify the molecular genetic cause of the disease in a 5-year-old male patient and histological, immunofluorescence as well as electron- and CARS-microscopic studies were performed to delineate the muscle pathology, which has so far only been studied in VAChT-deficient animal models. Results: ES unraveled compound heterozygous missense and nonsense variants (c.315G>A, p.Trp105* and c.1192G>C, p.Asp398His) in SLC18A3. Comparison with already-published cases suggests a more severe phenotype including impaired motor and cognitive development, possibly related to...
The American Journal of Human Genetics
Translational Psychiatry
Protocadherin-19 (PCDH19) pathogenic variants cause an early-onset seizure disorder called girls ... more Protocadherin-19 (PCDH19) pathogenic variants cause an early-onset seizure disorder called girls clustering epilepsy (GCE). GCE is an X-chromosome disorder that affects heterozygous females and mosaic males, however hemizygous (“transmitting”) males are spared. We aimed to define the neuropsychiatric profile associated with PCDH19 pathogenic variants and determine if a clinical profile exists for transmitting males. We also examined genotype- and phenotype–phenotype associations. We developed an online PCDH19 survey comprising the following standardized assessments: The Behavior Rating Inventory of Executive Function; the Social Responsiveness Scale, 2nd edition; the Strengths and Difficulties Questionnaire; and the Dimensional Obsessive-Compulsive Scale. Genetic, seizure, and developmental information were also collected. The survey was completed by patients or by caregivers on behalf of patients. Of the 112 individuals represented (15 males), there were 70 unique variants. Thirty-...
Human Genetics
Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein ... more Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), in...
Brain
KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models wi... more KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language de...
Tremor and Other Hyperkinetic Movements
Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify... more Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.
Nature Communications
KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynami... more KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients’ neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mR...
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
F1000 - Post-publication peer review of the biomedical literature
Coding variants represent many of the strongest associations between genotype and phenotype, howe... more Coding variants represent many of the strongest associations between genotype and phenotype, however they exhibit inter-individual differences in effect, termed variable penetrance. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from GTEx, we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian SNP using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Human Mutation
Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been des... more Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein‐damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic‐dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.
Neurobiology of Disease
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Uploads
Papers by Christel Depienne