GeNeXprESS

Non-invasive prenatal testing for low risk women¹

Though non-invasive prenatal testing using massively parallel sequencing of cell free fetal DNA has been in use in clinical practice since 2011, most of the study cohort and the subsequent data relates to high risk pregnancies. The high accuracy of these techniques for aneuploidy detection has been already proved in these cases. A study by Bianchi et al in a large cohort of women with uncomplicated singleton pregnancies has finally proved this can be a useful technique in the general low risk obstetric population as well. The negative predictive value of this screening has been estimated to be nearly 100% with a tenfold higher positive predictive value for trisomy 21. This would bring down substantially the number of procedures due to false positive results. Hence, it is likely to become the test of choice for antenatal screening as soon as the cost of the next generation sequencing technique comes down.

The other side of the coin²

In absolute numbers, female feticide especially in countries like India translates into elimination of up to half a million per year. Madan et al have reviewed the impact of prenatal testing on sex ratio in India providing insights into the alarming rate at which the sex ratio is falling every decade in India. Among children between 0 and 6 years, the sex ratio has fallen to 914, which is the lowest since records for this age group have been kept. In some states, it is even below 900. With the availability of home kits using pin prick blood samples, these easy to use tests may thus become a highly misused tool in India and China where female feticide and infanticides are rampant.

The perfect collaboration!³

Clinicians and scientists in Canada came together as they felt the necessity to provide molecular diagnosis to children with rare diseases for their clinical management as well as offer prenatal testing to families with these disorders. It was named as the FORGE (Finding of Rare Disease Genes) Canada Consortium and included their various genetic, science and innovation centres. Over a period of two years, they screened 264 disorders. Sixty seven genes not previously associated with human diseases (41 of which have been genetically or functionally validated, and 26 are being currently studied) were identified for 146 disorders. They have beautifully discussed the stepwise approach they have used for new gene discovery and its impact on patients and families with rare diseases. The most successful strategies for new gene discovery were: multiple unrelated individuals or families affected by the same recognizable condition and disorders in consanguineous families. The researchers have used two interesting resource tools. PhenoTips was used for phenotyping with standard terminology in very less time and the data was linked with genomic data in PhenomeCentral, an integrated portal developed to facilitate collaboration and gene discovery. The way to go for other countries and continents!

Guidelines for causality of sequence variants⁴

Even the laboratories with the most experienced personnel, most sophisticated bioinformatics tools and other techniques, are often unable to differentiate the actual disease causing variants from the normal human variations. Few recent studies have concluded that as many as 27% of sequence variants can be assigned as pathogenic when they were either polymorphisms or carried insufficient evidence of the pathogenicity. MacArthur et al. have come up with guidelines for the interpretation of pathogenicity of sequence variations. Determining the pathogenicity not only is important for diagnostic purposes but is equally important for the research as well. The guidelines are evidence based and are devised by a group of experts in the field of genomic research, clinical diagnostics and analysis under the US National Human Genome Research Institute. The implementation of these guidelines would in future require the need to establish updated public databases as well as population specific allele frequencies and large scale genotype data from these populations for well characterized diseases.

References