Publications by authors named "Silvia Carestiato"
Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder linked to haploinsufficiency of CREBBP (RSTS1) and EP300 (RSTS2) genes. Characteristic features often include distinctive facial traits, broad thumbs and toes, short stature, and various degrees of intellectual disability. The clinical presentation of RSTS is notably variable, making it challenging to establish a clear genotype-phenotype correlation, except for specific variants which cause the allelic Menke-Hennekam syndrome.
View Article and Find Full Text PDFAlexander disease (ALXDRD) is a rare neurodegenerative disorder of astrocytes resulting from pathogenic variants in the GFAP gene. The genotype-phenotype correlation remains elusive due to the variable expressivity of clinical manifestations. In an attempt to clarify the effects of GFAP variants in ALXDRD, numerous studies were collected and analyzed.
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- The study investigates the use of genomic DNA methylation analysis, or episignature profiling, in diagnosing neurodevelopmental disorders (NDDs) by evaluating two cohorts of patients: one with known pathogenic variants and another with uncertain mutations.
- In the validation group of 59 patients, 90% exhibited expected episignatures, although some variants displayed overlapping profiles due to similar clinical symptoms.
- In the test cohort of 38 patients, five cases identified novel pathogenic variants and confirmed diagnoses for conditions such as Cornelia de Lange syndrome, highlighting the potential of episignature analysis to tackle complex genetic diagnosis challenges.
Despite major advances in genome technology and analysis, >50% of patients with a neurodevelopmental disorder (NDD) remain undiagnosed after extensive evaluation. A point in case is our clinically heterogeneous cohort of NDD patients that remained undiagnosed after FRAXA testing, chromosomal microarray analysis and trio exome sequencing (ES). In this study, we explored the frequency of non-random X chromosome inactivation (XCI) in the mothers of male patients and affected females, the rationale being that skewed XCI might be masking previously discarded genetic variants found on the X chromosome.
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- The study identifies a new autosomal dominant disorder linked to loss-of-function variants in the CAPRIN1 gene, which plays a role in neuronal mRNA transport and translation, affecting cognitive and developmental functions.
- Out of 12 cases studied, patients exhibited a range of neurodevelopmental issues, including language impairments, intellectual disabilities, ADHD, and autism, along with various physical health problems.
- Using CRISPR-Cas9 technology, the researchers created CAPRIN1 deficient stem cells, finding that the loss of this gene leads to disrupted neuronal organization, reduced neuronal function, and impaired calcium signaling, suggesting significant impacts on brain development and function.
Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening.
Genes (Basel)
December 2020
Alexander disease (AxD) is a rare astrogliopathy caused by heterozygous mutations, either inherited or arising de novo, on the glial fibrillary acid protein (GFAP) gene (17q21). Mutations in the GFAP gene make the protein prone to forming aggregates which, together with heat-shock protein 27 (HSP27), αB-crystallin, ubiquitin, and proteasome, contribute to form Rosenthal fibers causing a toxic effect on the cell. Unfortunately, no pharmacological treatment is available yet, except for symptom reduction therapies, and patients undergo a progressive worsening of the disease.
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