De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease

Abstract

We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.

APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

“…ID fam, family code; MC, number of mutations carriers in the family; AOO, age of onset ranges in the family; DD, disease duration (at death or last examination); APOE, Apolipoprotein E genotype; F, familial; S, sporadic; Y, yes, U, unknown.* Indicates a previously reported de novo mutation in a sporadic case [20, 21, 40]. …”

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

“…The MARK4 variant was located in the linker domain and the VPS35 variant just 5 codons away from a mutation causing Parkinson disease and with demonstrated distinct functional effects [113,114] . The apparent specificity of these short regions and the weak probability that a variant would hit these regions in multiple individuals by chance may explain why there is currently no evidence of an association at the variant or gene levels.…”

“…Second, we performed WES in the 12 remaining trios and identified 12 nonsynonymous DNVs in 6 patients. The two de novo CNVs and 3 out of 12 nonsynonymous DNVs (in PSEN1 , VPS35 , and MARK4 ) targeted genes involved in a biological network centered on the Aβ peptide [113] . After computing the relative size of jointly covered bases of this a priori defined genetic network (323 genes) as well as estimating its relative mutability through the burden of inherited variants, we showed that this network was significantly enriched in amino acid-altering DNVs, compared to the rest of the exome.…”

“…These genes might never be identified by classical case-control analyses, even with huge sample sizes. We sampled 14 affected EOAD patient-unaffected parents' trios, for whom we performed CNV screening by array CGH and then WES, looking at DNVs [113] . In this sample, we identified the first de novo APP duplication and one de novo deletion within intron 1 of BACE2 .…”

Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds

“…Mutations in the PSEN1 gene account for the majority of AD-EOAD cases with 221 pathogenic mutations reported to date (http://www.alzforum.org/), including 6 deletions of PSEN1 exon 9 resulting either from splicing mutations (Perez-Tur et al, 1995;Sato et al, 1998;Rovelet-Lecrux et al, 2015) or genomic deletions (Prihar et al, 1999;Hiltunen et al, 2000;Smith et al, 2001).…”