New horizons in the diagnostic utility of genomic sequencing

30 Dec 2021

Achieving a precise diagnosis is a fundamental goal of medical practice. Recently with wider clinical use of genetic testing as part of the diagnostic evaluation, nephrologists have the challenging task of selecting the most suitable genetic test for each patient, and then applying the results into the appropriate clinical contexts, as the findings from renal biopsy are not completely accurate and cannot always provide a precise diagnosis as stated by Professor Katherine Benson from Royal College of Surgeons in Ireland.1 An accurate genetic diagnosis can result in changes in clinical judgment, understanding of pathological mechanisms, and confirming histological findings and treatment.1 In fact, large proportion of cases of interstitial nephritis are caused by genetic mutations including Mucin 1, cell surface associated, uromodulin, renin, hepatocyte nuclear factor-1 beta (HNF1B) and 10% of the adult cases of focal segmental glomerulosclerosis are caused by more than 50 genetic mutations, hence biopsy results tend to be non-specific, highlighting the need for genetic diagnosis.1 


Interestingly, an alternative diagnostic method is genomic sequencing which involves sequencing of patients’ DNA typically from blood or saliva samples followed by bioinformatic analysis to filter the diagnostic variants.1 The various types of short-read next-generation sequencing (NGS) include whole-exome sequencing (WES), targeted sequencing of gene panels and whole-genome sequencing (WGS) which can be used to diagnose patients with genetic diseases especially with monogenic disease.1 WGS often has a higher sequencing coverage and depth than WES resulting in a greater diagnostic yield.1 WES can be used to identify genetic cause in over 35% of the chronic kidney disease (CKD) families.1 However long-read NGS approaches are used for diagnosing the complex diseases.1 Many sequencing platforms employing NGS have been developed including pyrosequencing, Ion Torrent technology, Illumina, and single molecule real-time sequencing by PacBio, nanopore sequencing, etc.1


Although renal biopsy is considered a relatively safe procedure, it does have some risks associated with it, like bleeding, or in some cases biopsy might indeed not be possible if the patient has small organs or if the patient has only one kidney, and therefore genomic sequencing has provided new clinical insight which can be considered as a complementary diagnostic tool to renal biopsy for more accurate diagnosis.1


Prof. Benson assessed the diagnostic yield of targeted genomic sequencing for patients in their diagnostic journey, where biopsy results were not very accurate.1 She shared a case to demonstrate the benefits of genetic sequencing as diagnostic tool in a 44-year-old female with stage III CKD and a history of hematuria and proteinuria, and family history of microscopic hematurial with no visual or hearing features.1 The initial diagnosis with renal biopsy supported the diagnosis of Alport syndrome but was not conclusive and did not meet the diagnostic criteria for Alport syndrome in the patient, highlighting the need for genetic testing.1 Therefore, a confirmatory follow up genetic testing was recommended for the patient and her entire family.1 The results from genetic testing redefined the diagnosis provided by renal biopsy to X linked dominant (XLD) form of Alport syndrome in all the family members.1 These findings proved that both renal biopsy and genetic testing are valuable diagnostic tools, but they have their own limitations.1 She further stressed that although renal biopsy may not provide exact precision diagnostic, it can provide prognostic information for which the results can be obtained faster as compared to genetic testing.1 However, collagen related genetic disorders (COL4) are usually under-diagnosed with biopsy alone and therefore, genetic sequencing can help resolve this clinical diagnostic challenge, and the accurate diagnosis by genetic sequencing can actually facilitate the avoidance of toxic and inappropriate therapies.1


Prof. Benson further emphasized genetic sequencing is highly recommended in patients with family history of consistent renal disease, extra renal features with potential genetic cause, organ donation in families with CKD, and families with discordant age at ESRD.1 


Prof. Benson stated, while interpreting the results of genetic testing, it is important that international guidelines from the American College of Medical Genetics (ACMG) on variants pathogenicity are followed.1 The genetic data should be regularly reviewed to support the development of educational programs catered towards increased appreciation of using genetic tests, and technical acumen which may help with patient management and improve formal practical guidance for the use of genetic testing in nephrology practice.1 “Genomic sequencing should be performed before renal biopsy provided that the biopsy is not feasible or precise diagnosis is required, particularly when biopsy is likely not able to provide an accurate diagnosis.” Prof. Benson concluded.

Get access to our exclusive articles.