Australia and New Zealand renal gene panel testing in routine clinical practice of 542 families

Abstract

Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.

Fig. 1. Ages at referral by panel.

a Distribution of ages at referral in the pediatric cohort (n = 281 probands). b Distribution of ages at referral in the adult cohort (n = 271 probands). Each data point represents a proband (blue = male; red = female) referred for the relevant panel. Filled black points indicate outliers (points beyond 1.5 times the interquartile range above the upper hinge [75th percentile] or below the lower hinge [25th percentile]). Abbreviated panels are as follows: ADTKD autosomal dominant tubulointerstitial kidney disease, aHUS/C3 GN atypical hemolytic uremic syndrome-C3 glomerulonephritis, Alport Alport syndrome, ARPKD autosomal recessive polycystic kidney disease, BORS branchio-oto renal syndrome, CAKUT congenital anomalies of the kidney and urinary tract, Nephrotic nephrotic syndrome, NPHP & ciliopathies nephronophthisis & related ciliopathies.

Fig. 2. Age and gender distribution of 154 probands referred for atypical hemolytic uremic syndrome-C3 glomerulonephritis (aHUS/C3 GN) panel testing.

Referrals were processed between December 2013 and October 2019.

Fig. 3. Age and gender distribution of 90 probands referred for Alport syndrome panel testing.

Referrals were processed between December 2013 and October 2019.

Fig. 4. Diagnostic rate of pathogenic or likely pathogenic variants, stratified by panel.

Variant classification was based on 2015 ACMG guidelines. The number of families referred for each panel is shown along the x-axis. Abbreviated panels are as follows: ADTKD autosomal dominant tubulointerstitial kidney disease, aHUS/C3 GN atypical hemolytic uremic syndrome-C3 glomerulonephritis, Alport Alport syndrome, ARPKD autosomal recessive polycystic kidney disease, BORS branchio-oto renal syndrome, CAKUT congenital anomalies of the kidney and urinary tract, Nephrotic nephrotic syndrome, NPHP & ciliopathies nephronophthisis & related ciliopathies.

Fig. 5. Mutation types of pathogenic or likely pathogenic variants.

a Distribution of mutation types of pathogenic or likely pathogenic variants in the pediatric cohort (n = 281 probands). b Distribution of mutation types of pathogenic or likely pathogenic variants in the adult cohort (n = 271 probands). Variant classification was based on 2015 ACMG guidelines. Abbreviated mutation types are as follows: CNV, copy number variation, indels insertions or deletions.

Fig. 6. Diagnostic rate of pathogenic or likely pathogenic variants, stratified by panel and cohort.

There were 278 families with a pediatric proband and 266 families with an adult proband. Two families had both affected pediatric and adult probands. Variant classification was based on 2015 ACMG guidelines. Abbreviated panels are as follows: ADTKD autosomal dominant tubulointerstitial kidney disease, aHUS/C3 GN atypical hemolytic uremic syndrome-C3 glomerulonephritis, Alport Alport syndrome, ARPKD autosomal recessive polycystic kidney disease, BORS branchio-oto renal syndrome, CAKUT congenital anomalies of the kidney and urinary tract, Nephrotic nephrotic syndrome, NPHP & ciliopathies nephronophthisis & related ciliopathies.