Pia Zacher
A5016731275- Genetics and Neurodevelopmental Disorders
- Genomics and Rare Diseases
- Epilepsy research and treatment
- Genomic variations and chromosomal abnormalities
- Ion channel regulation and function
- Congenital heart defects research
- Autism Spectrum Disorder Research
- Cellular transport and secretion
- Chromatin Remodeling and Cancer
- Cardiac electrophysiology and arrhythmias
- RNA and protein synthesis mechanisms
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- RNA regulation and disease
- RNA modifications and cancer
- Peptidase Inhibition and Analysis
- Retinal Development and Disorders
- Glycosylation and Glycoproteins Research
- Genetic and rare skin diseases.
- Hereditary Neurological Disorders
- interferon and immune responses
- Protein Kinase Regulation and GTPase Signaling
- Chemical Reactions and Isotopes
- Hedgehog Signaling Pathway Studies
- Erythrocyte Function and Pathophysiology
Epilepsiezentrum Kleinwachau Gemeinnützige
2017-2024
Université Claude Bernard Lyon 1
2023
Centre National de la Recherche Scientifique
2023
Hospices Civils de Lyon
2023
Inserm
2023
University of Florence
2023
Leipzig University
2020-2023
Heidelberg University
2023
University Hospital Heidelberg
2023
Institut NeuroMyoGène
2023
PurposeTo define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 NPRL3 genes encoding GATOR1 complex, a negative regulator mTORC1 pathwayMethodsWe analyzed clinical genetic data 73 novel probands (familial sporadic) with epilepsy-related variants in GATOR1-encoding proposed new guidelines for interpretation variants.ResultsThe seizure phenotype consisted mostly focal seizures (e.g., hypermotor or frontal lobe 50%), mean age at onset 4.4 years, often...
Abstract We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with aim of describing clinical phenotypes related to effects. Six different subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); 2, intermediate 33, mild intellectual disability, partially pharmaco-responsive); 3, developmental epileptic...
PurposeGenetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly.MethodsWe investigated 150 adult/elderly individuals NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also exome sequencing (nsingle = 71, ntrios 24).ResultsWe identified (likely) pathogenic variants 71 cases (47.3%) comprising fragile X...
Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery causative genes. Through forward genetics approach selecting for defective vocalization in mice, we identified Kdm5a as candidate ASD gene. To validate our discovery, generated knockout mouse model ( -/- ) confirmed that inactivating disrupts vocalization. In addition, mice displayed repetitive behaviors, sociability deficits, cognitive...
Summary Severe early onset epilepsies are often caused by de novo pathogenic variants. Few studies have reported the frequency of somatic mosaicism in parents children with severe epileptic encephalopathies. Here we aim to investigate epilepsy alleged We tested parental genomic DNA derived from different tissues for 75 cases using targeted next‐generation sequencing. Five (6.6%) showed at minor allele frequencies 0.8%‐29% variant detected their offspring. Parental was observed following...
Abstract Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates molecular mechanism underlying disorder a Cux1 +/− mouse model. Through international collaboration, we assembled phenotypic information for 34 individuals (23 unpublished individuals). We analyze brain expression susceptibility to epilepsy mice. describe individuals, from which 30...
Knowledge of the natural history CDKL5 deficiency disorder (CDD) is limited to results cross-sectional analysis largely pediatric cohorts. Assessment outcomes in adulthood critical for clinical decision-making and future precision medicine approaches but challenging because diagnostic gap duration follow-up that would be required prospective studies. We aimed delineate retrospectively from adulthood. analyzed data about an international cohort 67 adults with CDD. demographic, phenotypic,...
Germline variants that disrupt components of the epigenetic machinery cause syndromic neurodevelopmental disorders. Using exome and genome sequencing, we identified de novo in KDM2A , a lysine demethylase crucial for embryonic development, 18 individuals with developmental delays and/or intellectual disabilities. The severity ranged from learning disabilities to severe disability. Other core symptoms included feeding difficulties, growth issues such as intrauterine restriction, short stature...
Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical molecular data on a large cohort.Clinical symptoms for 41 novel 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, standardized grouped into non-truncating likely gene-disrupting (LGD) variants....
is one of the most frequently mutated genes in intellectual disability cohorts. Thus, far few adult-aged patients with
Asparagine-linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying recurrent ALG13 de novo variant, p.(Asn107Ser), normal transferrin electrophoresis.We delineate phenotypic spectrum 38 individuals, 37 girls one boy, 16 them novel 22 published, most common pathogenic variant p.(Asn107Ser) additionally report three individuals other likely...
Introduction Pigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on role for lysosomal signalling in embryonic stem cell differentiation, mutations X-linked transcription factor 3 ( TFE3 ) have recently been reported five patients. Functional analysis suggested these to result ectopic nuclear gain functions. Materials methods Subsequent...
Pathogenic variants in
Abstract Objective The postsynaptic density protein of excitatory neurons PSD‐95 is encoded by discs large MAGUK scaffold 4 ( DLG4 ), de novo pathogenic variants which lead to ‐related synaptopathy. major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy present in 50% the individuals, it has not been investigated detail. We describe here phenotypic spectrum associated comorbidities...
The two aims of this study were (i) to describe and expand the phenotypic spectrum PIGT deficiency in affected individuals harboring c.1582G>A; p.Val528Met or c.1580A > G; p.Asn527Ser variant either homozygous compound heterozygous state, (ii) identify potential genotype-phenotype correlations any differences disease severity among with without variants. existing literature was searched A detailed assessment performed 25 (both novel previously published) We compared between...
Abstract Background An identical homozygous missense variant in EIF3F , identified through a large-scale genome-wide sequencing approach, was reported as causative nine individuals with neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic molecular spectrum of EIF3F- related we examined independent patients. Results 21 patients were one compound heterozygous for...
Background and ObjectivesHeterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports published so far describing pathogenic of this gene patients epilepsy intellectual disability (ID). In study, we aimed delineate the phenotype RORB provide arguments favor pathogenicity variants.MethodsThrough an international collaboration, analyzed seizure characteristics, EEG data, genotypes a...
Abstract The 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals. underlying basis of the variable phenotype remains elusive. We analyzed gene expression using blood three individuals with and brain cortex tissue ten mice Df[h15q13]/+. assessed differentially expressed genes (DEGs), protein–protein interaction (PPI) functional modules, in developmental stages. deleted genes’ haploinsufficiency was not transcriptionally compensated,...