Blog entry by Meguid El Nahas
Kidney Int. 2014 Mar 5. doi: 10.1038/ki.2014.48. [Epub ahead of print]
Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing.
Brown EJ1, Pollak MR2, Barua M3.
The haploid human genome is composed of three billion base pairs, about one percent of which consist of exonic regions, the coding sequence for functional proteins, also now known as the 'exome'. The development of next-generation sequencing makes it possible from a technical and economic standpoint to sequence an individual's exome but at the cost of generating long lists of gene variants that are not straightforward to interpret. Various public consortiums such as the 1000 Genomes Project and the NHLBI Exome Sequencing Project have sequenced the exomes and a subset of entire genomes of over 2500 control individuals with ongoing efforts to further catalog genetic variation in humans.1 The use of these public databases facilitates the interpretation of these variant lists produced by exome sequencing and, as a result, novel genetic variants linked to the disease are being discovered and reported at a record rate. However, the interpretation of these results and their bearing on diagnosis, prognosis, and treatment is becoming even more complicated. Here, we discuss the application of genetic testing to individuals with focal and segmental glomerulosclerosis (FSGS), taking a historical perspective on gene identification and its clinical implications along with the growing potential of next-generation sequencing.Kidney International advance online publication, 5 March 2014; doi:10.1038/ki.2014.48.
COMMENTS BY PROF SOLIMAN:
This is a recently published, and a must read, review by Martin Pollak and colleagues. It takes the readership smoothly through the “uneasy” world of genetic testing in nephrotic syndrome (NS) and FSGS: why, when, how, who, which?
The authors go through the genetic causes of NS and FSGS including slit diaphragm, actin cytoskeleton, nuclear, glomerular basement membrane, and other genes e.g. APOL1. Nevertheless the authors did not come across the mitochondrial genes, an important entity being potentially treatable, as their main focus was nonsyndromic NS/FSGS.
Not only clinical implications of identifying a disease causing mutation in NS patient as to therapeutic intervention and transplantation strategy is discussed, but also the highly controversial area of testing the clinically unaffected members of a family with hereditary NS and the psychological ramifications that come along!
It all boils down to the wise and thoughtful use of genetic testing with considerations of its risks and benefits, and an understanding of its limitations in general as well as advantages and limitations of different procedures employed: Sanger sequencing, exome or genome sequencing, and the targeted sequencing by using panels of genes which has recently been increasingly implemented. In the latter, sequencing a panel of genes rather than the entire exome or genome allows the clinician/researcher to focus, with less complex, less time consuming and rather cheaper data interpretation.
Gained knowledge from this fascinating area of research in molecular genetics is immensely and rapidly growing, perhaps more than any other field in medicine. DNA sequencing technology is advancing at such a rapid pace, yet the challenge will always be how to translate this knowledge in terms of elucidating the pathogenesis of variable and complex renal diseases, in the best interest of affected patients and their families.