SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in São Paulo

Abstract

OBJECTIVES: High-throughput sequencing of genomes, exomes, and disease-focused gene panels is becoming increasingly common for molecular diagnostics. However, identifying a single clinically relevant pathogenic variant among thousands of genetic polymorphisms is a challenging task. Publicly available genomic databases are useful resources to filter out common genetic variants present in the population and enable the identification of each disease-causing variant. Based on our experience applying these technologies at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, Brazil, we recognized that the Brazilian population is not adequately represented in widely available genomic databases. METHODS: Here, we took advantage of our 5-year experience as a high-throughput sequencing core facility focused on individuals with putative genetic disorders to build a genomic database that may serve as a more accurate reference for our patient population: SELAdb. RESULTS/CONCLUSIONS: Currently, our database comprises a final cohort of 523 unrelated individuals, including patients or family members managed by different clinics of HCFMUSP. We compared SELAdb with other publicly available genomic databases and demonstrated that this population is very heterogeneous, largely resembling Latin American individuals of mixed origin, rather than individuals of pure European ancestry. Interestingly, exclusively through SELAdb, we identified a spectrum of known and potentially novel pathogenic variants in genes associated with highly penetrant Mendelian disorders, illustrating that pathogenic variants circulating in the Brazilian population that is treated in our clinics are underrepresented in other population databases. SELAdb is freely available for public consultation at: http://intranet.fm.usp.br/sela

High-throughput splicing assays identify missense and silent splice-disruptivePOU1F1variants underlying pituitary hormone deficiency

“…Combined with conventional Sanger sequencing in another family, this revealed four missense variants in exon 2 of the POU1F1 beta isoform, each in an unrelated family ( Figure 1A, 2A ). The four patient POU1F1 missense variants are absent from gnomAD and in-house population-matched exome databases 39,40 , and they are predicted to be damaging by several bioinformatic algorithms ( Table 1 ). Remarkably, these variants clustered in four consecutive codons: c.148T>G (p.S50A), c.152T>G (p.I51S), c.155T>G (p.L52W), and c.157T>G (p.S53A) in NM 001122757.3 ( Table 1 ).…”

Genetic and clinical aspects of paediatric pheochromocytomas and paragangliomas

“…The exome and the targeted panel sequencing data were screened for rare variants with minor allele frequency <0.1% in the public databases: Genome Aggregation Database, 17 1000 Genomes, 18 the Brazilian population database 19 and database of exonic variants in a Brazilian population referred to as a quaternary medical centre in São Paulo 20 . This study then selected the rare variants located in the exonic and consensus splice‐site regions.…”

Allelic Variants in Established Hypopituitarism Genes Expands Our Knowledge of Phenotypic Spectrum

“…Exome and panel variant sequencing analysis were similar, as they were performed in isolated patients. The filtering pipeline took into consideration exonic and splice site regions, as well as Minor Allele Frequency (MAF) of less than 1% in international and national populational databases: gnomAD (gnomad.broadinstitute.org), 1000 Genomes, ABraOM (abraom.ib.usp.br) 16 and internal database SELAdb (intranet.fm.usp.br/sela) 17 . First, homozygous variants were considered assuming an autosomal recessive disorder.…”