Abstract Precision Medicine emerges from the genomic paradigm of health and disease. For precise molecular diagnoses of genetic diseases, we must analyze the Whole Exome (WES) or the Whole Genome (WGS). By not needing exon capture, WGS is more powerful to detect single nucleotide variants and copy number variants. In healthy individuals, we can observe monogenic highly penetrant variants, which may be causally responsible for diseases, and also susceptibility variants, associated with common polygenic diseases. But there is the major problem of penetrance. Thus, there is the question of whether it is worthwhile to perform WGS in all healthy individuals as a step towards Precision Medicine. The genetic architecture of disease is consistent with the fact that they are all polygenic. Moreover, ancestry adds another layer of complexity. We are now capable of obtaining Polygenic Risk Scores for all complex diseases using only data from new generation sequencing. Yet, review of available evidence does not at present favor the idea that WGS analyses are sufficiently developed to allow reliable predictions of the risk components for monogenic and polygenic hereditary diseases in healthy individuals. Probably, it is still better for WGS to remain reserved for the diagnosis of pathogenic variants of Mendelian diseases.

Abstract Deletion-induced hemizygosity may unmask deleterious autosomal recessive variants and be a cause of the phenotypic variability observed in microdeletion syndromes. We performed complete exome sequencing (WES) analysis to examine this possibility in a patient with 1p13.2 microdeletion. Since the patient displayed clinical features suggestive of Noonan Syndrome (NS), we also used WES to rule out the presence of pathogenic variants in any of the genes associated with the different types of NS. We concluded that the clinical findings could be attributed solely to the 1p13.2 haploinsufficiency. Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS. In all these cases, the deleted segment included the NRAS gene. Gain-of-function mutations of NRAS gene are causally related to NS type 6. Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences. The same phenomenon has been described for two other genes belonging to the Ras/MAPK pathway: MAP2K2 and SHOC2. In conclusion, we here report genotype-phenotype correlations in patients with chromosome 1p13.2 microdeletions and we propose that NRAS may be a critical gene for the NS characteristics in the patients.

O conceito de 'raça' faz parte do arcabouço canônico da medicina, associado à idéia de que cor e/ou ancestralidade biológica são relevantes como indicadores de predisposição a doenças ou de resposta a fármacos. Essa posição decorre de uma visão tipológica de raças humanas. O baixo grau de variabilidade genética e de estruturação da espécie humana é incompatível com a existência de raças como entidades biológicas e indica que considerações de cor e/ou ancestralidade geográfica pouco ou nada contribuem para a prática médica, especialmente no cuidado do paciente individual. Mesmo doenças ditas 'raciais', como a anemia falciforme, decorrem de estratégias evolucionárias de populações expostas a agentes infecciosos específicos. Para Paul Gilroy, o conceito social de raça é 'tóxico', contamina a sociedade como um todo e tem sido usado para oprimir e fomentar injustiças, mesmo dentro do contexto médico.

As part of medicine's canonical framework, the concept of race has been associated with the idea that color and/or biological ancestry are relevant indicators of a predisposition to a certain disease or reaction to drugs. This stance derives from a typological view of human races. The low level of genetic variability and of structuring of the human species is incompatible with the existence of races as biological entities and tells us that color and/or geographic ancestry have little or nothing useful to contribute to medical practice, particularly when it comes to caring for an individual patient. We show that even so-called racial diseases like sickle cell anemia are really the product of evolutionary strategies used by populations exposed to specific infectious agents, whose territories have no unequivocal relation with either color or continental origin. Furthermore, in the words of sociologist Paul Gilroy, the social concept of race is "toxic," contaminating society as a whole, and it has been used to oppress and to foster injustice, even within a medical context.

The human nuclear protein RbAp48 is a member of the tryptophan/aspartate (WD) repeat family, which binds to the retinoblastoma (Rb) protein. It also corresponds to the smallest subunit of the chromatin assembly factor and is able to bind to the helix 1 of histone H4, taking it to the DNA in replication. A cDNA homologous to the human gene RbAp48 was isolated from a Schistosoma mansoni adult worm library and named SmRbAp48. The full length sequence of SmRbAp48 cDNA is 1036 bp long, encoding a protein of 308 amino acids. The transcript of SmRbAp48 was detected in egg, cercariae and schistosomulum stages. The protein shows 84% similarity with the human RbAp48, possessing four WD repeats on its C-terminus. A hypothetical tridimensional structure for the SmRbAp48 C-terminal domain was constructed by computational molecular modeling using the b-subunit of the G protein as a model. To further verify a possible interaction between SmRbAp48 and S. mansoni histone H4, the histone H4 gene was amplified from adult worm genomic DNA using degenerated primers. The gene fragment of SmH4 is 294 bp long, encoding a protein of 98 amino acids which is 100% identical to histone H4 from Drosophila melanogaster.

We have initiated a gene discovery program in Schistosoma mansoni based on the technique of Expressed Sequence Tags (ESTs), i.e. partial sequences of cDNAs obtained from single passes in automatic DNA sequencers. ESTs can be used to identify genese onf the basis of their homology whith sequences from other species deposited in DNA or protein databases. Trasncripts with sequences without matches in teh databases may represent novel parasite-specific genes. This approach has shown to be very efficient and in less than two years a broad range of novel genes has already been ascertained, more than doubling the number of known S. mansoni genes.