Abstract
The synchronized advent of high-throughput next-generation sequencing technology and knowledge of the human genome has rendered exponential contributions to our understanding of the pathophysiology of glomerular kidney diseases. A genetic diagnosis can now be made or confirmed in about two-thirds of the suspected inherited glomerular diseases. Next-generation sequencing is adept at identifying single nucleotide variations and small insertions or deletions that constitute majority of the disease-causing mutations. Description of the complete mutation spectrum in syndromic glomerulopathies may require the use of both sequencing and cytogenetic methods to detect large structural DNA variation in addition to single nucleotide changes. The enthusiastic application of genetic and genomic knowledge to inherited glomerular diseases has uncovered anticipated and unforeseen challenges mainly related to the biological interpretation of variants of uncertain significance and the limited benefit on clinical management for the individual patient when a diagnosis is obtained. To attain the ultimate goal of transforming clinical decision-making based on accurate genetic diagnosis using genomic information, these challenges need to be addressed. Till then, the glory of genomic medicine stands the test of time in this gilded age of genomic advancements.
Highlights
Glomerular diseases constitute almost a quarter of etiologically defined end-stage renal disease (ESRD) in children (22%; similar to CAKUT), with focal segmental glomerulosclerosis (FSGS) being the most common individual diagnosis (12%) associated with pediatric ESRD in the 2017 USRDS annual data report [1]
The proportion of ESRD of unknown or unspecified cause is significant at 21% and steadily increases with age, ranging from 11% between 0 and 4 years of age up to 27% in the 18–21-year age group
Unsolved and misdiagnosed glomerular disease poses relevant clinical challenges. It is often classified as idiopathic, portrays substantial morbidity related to proteinuria and progressive chronic kidney disease (CKD) requiring long-term follow-up and care. These characteristics identify glomerular conditions as the most important group where genetic diagnosis made using recent genomic advancements in the field can be best utilized for maximum clinical advantage
Summary
Glomerular diseases constitute almost a quarter of etiologically defined end-stage renal disease (ESRD) in children (22%; similar to CAKUT), with focal segmental glomerulosclerosis (FSGS) being the most common individual diagnosis (12%) associated with pediatric ESRD in the 2017 USRDS annual data report [1]. Molecular cytogenetic tests, including fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) known as chromosomal microarray analysis (CMA), are a good adjunct to karyotyping and conventional cytogenetics [3] These are hybridization assays that use fluorescent complementary DNA probes to detect or demonstrate the lack of a segment of DNA sequence and can detect CNVs that may represent an important component of the mutation spectrum of certain diseases especially for syndromic conditions. Identification of large deletions by next-generation sequencing though possible, the sensitivity depends on the read depth of the region requiring additional vigilance and may merit additional communication with the clinical lab regarding such analysis [10] This may be useful in cases with syndromic or multi-systemic involvement where deletion of a genomic segment including the entire or more than one gene is suspected. European guidelines recommend validation of CNV in exome data by genome-wide array analysis or another suitable technique [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
