A recent article in The NewEngland Journal of Medicinetitled “Diagnostic Utilityof Exome Sequencing for KidneyDisease” offers us unique insightsinto the future diagnostic evaluationof chronic kidney disease (CKD).The most important takeawaysfrom the article by Groopman etal. are that nearly 1 in 10 patientswith CKD have a genetic causeof kidney disease, which often isundiagnosed, and that whole exomesequencing can be helpful in making these diagnoses.
The investigators undertook whole exome sequencing of 3315individuals with CKD. In whole exome sequencing, the nucleotidesequence of the human genome that codes for proteins (exons)is determined. Results were compared with exome sequences ofthousands of healthy individuals to determine genetic differences.The investigators focused attention on genes that were expressedin the kidney and were likely to be relevant to kidney pathology.
The study found that 307 patients (9.3%) suffered from a monogenicdisorder as the cause of kidney disease, with 66 differentgenetic conditions identified. As one would expect, autosomaldominant polycystic kidney disease was the most common cause,with 97 individuals affected (accounting for 2.9% of cases of kidneydisease and 31% of cases with inherited kidney disease). The nextmost common causes of inherited kidney disease were mutations inthe COL4A3, COL4A4, and COL4A5 genes, found in 91 individuals(30% of inherited kidney disease). Importantly, 39 of the 66 geneticdisorders identified were each found in only a single individual.Uncommon genetic disorders included mutations in the gene encodinghepatocyte nuclear factor-1 beta and branchio-oto-renal syndrome.
These results point to a future when whole exome sequencingwill be the method of choice for identifying genetic causes ofCKD. Instead of targeted gene analysis (for example, in Alportsyndrome or polycystic kidney disease), clinicians will screenthe whole genome at once. Study findings should encouragenephrologists to take a more thorough family history and givegreater consideration to inherited kidney diseases in the differentialdiagnosis. Nephrologists should more actively pursue a geneticdiagnosis, especially when multiple family members have CKD.
Although many of the inherited kidney diseases are not currentlytreatable, a proper genetic diagnosis will provide families with thecause of CKD, avoid unnecessary kidney biopsies that may not bediagnostic, and allow for screening of family members as potentialkidney donors. This year, let us resolve to think more not just aboutour own families, but the families we see with kidney disease.