Publications by authors named "Kilan Le Guennec"
Objective: The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes.
Methods: We performed a gene-based collapsing test of rare protein-truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of 2 publicly available large-scale databases, gnomAD and TOPMed.
Article Synopsis
- * The results showed a high positive predictive value (PPV) of 87.8% from gene panel data and 86.4% from whole-exome sequencing, with perfect sensitivity and specificity for a subset of gene comparisons.
- * The findings suggest that adopting an NGS-only approach could be more cost-effective and provide stable diagnostic yields, with the CANOES workflow enabling detection of CNVs at a detailed exon level that may be missed by other methods.
Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer's disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included.
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- Researchers conducted whole-exome and whole-genome sequencing on nearly 3,000 Alzheimer’s disease cases and controls from France to investigate genetic associations.
- They found significant links between early-onset Alzheimer’s (EOAD) risk and rare variants in three specific genes: SORL1, TREM2, and ABCA7, but not in late-onset Alzheimer’s (LOAD).
- The study reaffirmed previous findings on these genes and highlighted that variations in TREM2, SORL1, and ABCA7 each explain a small portion (1.1% to 1.5%) of EOAD heritability, much less than the substantial impact of the APOE ε4 variant (9.12
Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis. Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10.
View Article and Find Full Text PDFObjective: To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting.
Methods: We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls.
Results: After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.
Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years.
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