Exome Sequencing Opens a New Chapter in CKD

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Study results point to a future when whole exome sequencing will be the method of choice for identifying genetic causes of CKD.
Study results point to a future when whole exome sequencing will be the method of choice for identifying genetic causes of CKD.

A recent article in The New England Journal of Medicine titled “Diagnostic Utility of Exome Sequencing for Kidney Disease” offers us unique insights into the future diagnostic evaluation of chronic kidney disease (CKD). The most important takeaways from the article by Groopman etal. are that nearly 1 in 10 patients with CKD have a genetic cause of kidney disease, which often is undiagnosed, and that whole exome sequencing can be helpful in making these diagnoses. 

The investigators undertook whole exome sequencing of 3315 individuals with CKD. In whole exome sequencing, the nucleotide sequence of the human genome that codes for proteins (exons) is determined. Results were compared with exome sequences of thousands of healthy individuals to determine genetic differences. The investigators focused attention on genes that were expressed in the kidney and were likely to be relevant to kidney pathology. 

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The study found that 307 patients (9.3%) suffered from a monogenic disorder as the cause of kidney disease, with 66 different genetic conditions identified. As one would expect, autosomal dominant polycystic kidney disease was the most common cause, with 97 individuals affected (accounting for 2.9% of cases of kidney disease and 31% of cases with inherited kidney disease). The next most common causes of inherited kidney disease were mutations in the COL4A3, COL4A4, and COL4A5 genes, found in 91 individuals (30% of inherited kidney disease). Importantly, 39 of the 66 genetic disorders identified were each found in only a single individual. Uncommon genetic disorders included mutations in the gene encoding hepatocyte nuclear factor-1 beta and branchio-oto-renal syndrome. 

These results point to a future when whole exome sequencing will be the method of choice for identifying genetic causes of CKD. Instead of targeted gene analysis (for example, in Alport syndrome or polycystic kidney disease), clinicians will screen the whole genome at once. Study findings should encourage nephrologists to take a more thorough family history and give greater consideration to inherited kidney diseases in the differential diagnosis. Nephrologists should more actively pursue a genetic diagnosis, especially when multiple family members have CKD. 

Although many of the inherited kidney diseases are not currently treatable, a proper genetic diagnosis will provide families with the cause of CKD, avoid unnecessary kidney biopsies that may not be diagnostic, and allow for screening of family members as potential kidney donors. This year, let us resolve to think more not just about our own families, but the families we see with kidney disease.

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