Biology subjects

Striano, P.

Publications and source records attributed to Striano, P..

5 recordsLinked to original sources

bioRxiv2025

Predicting Drug Response with Multi-Task Gradient-Boosted Trees in Epilepsy

MotivationDespite the availability of numerous anti-seizure medications (ASMs), drug resistance remains a major issue for people with epilepsy. The probability of achieving seizure freedom diminishes with each unsuccessful drug trial, and the impact of genetic and clinical markers on ASM response remains unclear. To address this issue, we used state-of-the-art machine learning (ML) methods to predict the response of people with epilepsy to individual ASMs based on their clinical and genomic information. ResultsTo overcome data sparsity for less common drugs, we implement a multi-task (MT) learning approach for gradient-boosted trees (GBTs), assuming that predicting responses to different ASMs involves similar tasks. This strategy allows models for less prevalent drugs to leverage the more abundant data available for other drugs during training. The proposed model outperforms individual and combined drug-response predictions for most drugs. Our findings identify key genomic and clinical features influencing drug response, enhancing understanding of individual drug responses in people with epilepsy, and aiding clinicians in making informed treatment decisions. Availability and ImplementationDue to privacy reasons data is not publically available. The code will be made available upon acceptance under https://github.com/pfeiferAI/MT-GBT

bioinformatics↗

bioRxiv2022

Human mutations in SLITRK3 implicated in GABAergic synapse development in mice

We report on biallelic homozygous and monoallelic de-novo variants in SLITRK3 in 3 unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, we bring additional evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG, as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, our results exhibit impaired development of peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. Our study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.

genetics↗

bioRxiv2021

Determining pathogenicity of variants of uncertain significance and identification of a founder variant in the epilepsy-associated gene, SZT2

Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTOR signaling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions. We report a cohort of twelve individuals with biallelic SZT2 variants and phenotypes consistent with SZT2-related neurodevelopmental disorder. The majority of this cohort contained one or more SZT2 variants of uncertain significance (VUS). We developed a novel individualized platform to functionally characterize SZT2 VUSs. We identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis determined this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Overall, we present a FACS-based rapid assay to distinguish pathogenic variants from VUSs in SZT2, using an approach that is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1/2, MTOR and NPRL2/3.

genetics↗

bioRxiv2019

Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

genetics↗

bioRxiv2017

The Spectrum Of De Novo Variants In Neurodevelopmental Disorders With Epilepsy

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.

genetics↗