Exomic variants of an elderly cohort of Brazilians in the ABraOM database

Abstract

Brazilians are highly admixed with ancestry from Europe, Africa, America, and Asia and yet still underrepresented in genomic databanks. We hereby present a collection of exomic variants from 609 elderly Brazilians in a census-based cohort (SABE609) with comprehensive phenotyping. Variants were deposited in ABraOM (Online Archive of Brazilian Mutations), a Web-based public database. Population representative phenotype and genotype repositories are essential for variant interpretation through allele frequency filtering; since elderly individuals are less likely to harbor pathogenic mutations for early- and adult-onset diseases, such variant databases are of great interest. Among the over 2.3 million variants from the present cohort, 1,282,008 were high-confidence calls. Importantly, 207,621 variants were absent from major public databases. We found 9,791 potential loss-of-function variants with about 300 mutations per individual. Pathogenic variants on clinically relevant genes (ACMG) were observed in 1.15% of the individuals and were correlated with clinical phenotype. We conducted incidence estimation for prevalent recessive disorders based upon heterozygous frequency and concluded that it relies on appropriate pathogenicity assertion. These observations illustrate the relevance of collecting demographic data from diverse, poorly characterized populations. Census-based datasets of aged individuals with comprehensive phenotyping are an invaluable resource toward the improved understanding of variant pathogenicity.

RareRELNvariants affect Reelin-DAB1 signal transduction in autism spectrum disorder

“…These variants were also detected using targeted next‐generation sequencing of a panel of autism‐related genes. The c.7538C > G (p.Ser2513Cys) substitution, inherited from the father, is present in dbSNP (rs114647348), is rare in control population databases (MAF < 0.004) and in control individuals of matched ancestry (ABraOM database; Naslavsky et al., ), frequency 0.0016), and shows a CADD score of 21. The c.7634C > T (p.Ala2545Val) substitution, inherited from the mother, is present in dbSNP (rs116634494), is very rare in control population databases (MAF < 0.0005) and in ancestry matched controls (ABraOM database, frequency 0.0008) and has a CADD score of 25.…”

Development and validation of a variant detection workflow for BRCA1 and BRCA2 genes and its clinical application based on the Ion Torrent technology

“…This is of special interest, since one of the most critical points of this workflow is the definition between a pathogenic mutation and a benign variant. Additionally, the generation of specific databases is important for populations like the one we have in Brazil due to its admixture, with different representations of African, European, and Native American variant frequencies [15]. It is interesting to note a slight clusterization of BRCA2 variants near the OB3 domain.…”

APOBEC‐mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV‐positive gastric cancer

“…Extensive filtering was applied to remove low‐mapping quality, as well as strand and position bias. Further residual germline variants were filtered out using the database of germline mutations of the Exome Aggregation Consortium (ExAC) and the Online Archive of Brazilian Mutations (ABraOM) …”