Identification of novel pathogenic genes of childhood epileptic encephalopathies

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 27, 2023

Abstract Background Epileptic encephalopathy is a devastating epilepsy with etiologies largely elusive, despite whole-gene/exon sequencing of large cohorts. This study targeted the genetic causes childhood epileptic encephalopathy, typically Lennox-Gastaut syndrome (LGS) featured by age-dependent onset and characteristic clinical manifestations. Methods Trio-based whole-exome was performed in 235 LGS cases individualized analyses on each trio explainable inheritance origin stratified frequency filtration gene four aspects, specified statistical including that compound heterozygous variants controls 1942 asymptomatic parents. Animal models were used to validate roles novel candidate genes. Results We identified three causative genes, SBF1 de novo , CELSR2 recessive, TENM1 X-linked recessive variants. Significantly higher excesses biallelic variants, aggregated variant frequencies detected. Phenotype severity/outcome correlated genotype these In Drosophila knockdown genes showed increased seizure-like behavior firing excitatory neurons. Sbf1 knockout zebrafish behavior, premature death, Celsr2 mice spontaneous seizures epileptiform discharges. Additional 42 as pathogenic evidence aspects/statistics. Conclusions suggests are highlights implications phenotype subclassification protocol identifying human diseases.

Language: Английский

---

Epilepsy-associated genes: discovery, clinical significance, and underlying principles of genetic medicine

Seizure, Journal Year: 2024, Volume and Issue: 116, P. 1 - 3

Published: Jan. 3, 2024

Language: Английский

---

CCDC88C variants are associated with focal epilepsy and genotype–phenotype correlation

Clinical Genetics, Journal Year: 2024, Volume and Issue: 105(4), P. 397 - 405

Published: Jan. 3, 2024

Abstract CCDC88C gene, which encodes coiled‐coil domain containing 88C, is essential for cell communication during neural development. Variants in the caused congenital hydrocephalus, some accompanied by seizures. In patients with epilepsy without acquired etiologies, we performed whole‐exome sequencing (trio‐based). Two de novo and two biallelic variants were identified four cases focal (partial) epilepsy. These did not present or had low frequencies gnomAD populations predicted to be damaging multiple computational algorithms. Patients presented adult‐onset epilepsy, whereas displayed infant‐onset They all responded well anti‐seizure medications seizure‐free. Further analysis showed that located at crucial domains, one paired outside other variant a non‐classical splicing domain, suggesting sub‐molecular effect. associated hydrocephalus truncated, epilepsy‐associated mainly missense, proportion of was significantly higher than hydrocephalus‐associated variants. potentially favorable outcome. The underlying mechanisms phenotypic variation may correlation between genotype phenotype.

Language: Английский

---

Clinical concordance evaluation of the causality of sequence variants

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 21, 2023

Abstract Interpreting the sequence variants is a scientific challenge, as well realistic task in clinical practice. The pathogenicity of depends not only on damage but also genetic dependent quantity (GDQ, quantitative function required for normal life) that differs each gene, was considered previous protocols. We developed concordance evaluation (CCE) framework to evaluate pathogenicity/causality by comparing clinical-genetic feature patient with pathogenic candidate including phenotype specificity, genotype, genotype-phenotype (severity) correlation, and inheritance, which are associated GDQ. In 337 patients epilepsy test, 70 were evaluated pathogenic/likely American College Medical Genetics Genomics guideline (ACMG). CCE identified all these variants, excluded one variant. additional 13 possible-causative, likely-causative, two causative homozygous variant MFSD8 ceroid lipofuscinosis, be uncertain significant ACMG. individualized criteria features individual being potentially practical protocol medicine future.

Language: Английский

---

Clinical concordance evaluation of the causality of sequence variants

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 18, 2023

Abstract Interpreting sequence variants is a scientific challenge as well realistic task in clinical practice. The pathogenicity of variant depends on not only its damage but also the genetic dependent quantity (GDQ, quantitative function required for normal life) that differs each gene was considered previous protocols. We developed concordance evaluation (CCE) framework to evaluate pathogenicity/causality by comparing and features patient with pathogenic candidate genes, including phenotype specificity, genotype, genotype-phenotype (severity) correlation, inheritance, which are associated GDQ. In 337 patients epilepsy testing, 70 were evaluated pathogenic/likely American College Medical Genetics Genomics guidelines (ACMG). CCE identified all these excluded one variant. an additional 13 possibly-causative, likely-causative, two causative variants, homozygous MFSD8 ceroid lipofuscinosis, “uncertain significance” ACMG. individualized criteria clinical/genetic abnormalities individual potentially practical protocol medicine.

Language: Английский

---