Proposed Large Gene Panel Analysis Helps Diagnose Alport, Other Inherited Kidney Diseases, Study Shows

A new approach involving the analysis of a panel of 140 genes previously linked to kidney disease helped diagnose patients with cystic and glomerular inherited kidney diseases and determine the risk of disease progression, a study has found.

This newly proposed, noninvasive tool can assist in the diagnosis of some of the most common inherited kidney diseases, such as Alport syndrome, with high sensitivity and effectiveness.

The genetic test was described in the study, “A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases,” published in the journal Kidney International.

Cystic kidney diseases are characterized by the formation of cysts that disrupt the normal structure of nephron — the part of the kidney where the last filtration steps take place to form urine.

On the other hand, glomerular kidney diseases are commonly detected by increased levels of protein and blood in the urine due to structural defects of the kidney’s blood filtration structure, in particular affecting the glomerular basement membrane, or the podocytes.

Alport syndrome is the most common glomerular kidney disease, and is caused by genetic mutations affecting the COL4A5, COL4A3, or COL4A4 genes.

About 100 genes have been identified as causing or significantly contributing to the development of cystic kidney disease, and 50 genes have been linked to glomerular kidney disease.

“Clinicians are being confronted with an expanding phenotypic [presentation] spectra of inherited kidney diseases as well as a constantly growing list of disease-causing genes. Therefore, broader diagnostic approaches are required,” the researchers wrote.

Led by researchers at Instituto de Investigación Carlos III in Barcelona, Spain, the team analyzed the sequence of 140 genes related to cystic and glomerular kidney diseases in 421 patients with known or suspected kidney disease.

They first performed the analysis in samples collected from 116 patients who were known to be carriers of genetic mutations associated with kidney disease. All the genetic variants were detected by the selected panel of 140 genes, with the exception of one mutation in the PKD1 gene of one patient. This showed that the panel was able to detect all kidney disease-linked genetic variants with a sensitivity of 99%.

Next, the team used the same genetic panel analysis to evaluate 305 patients who were suspected of having inherited cystic and glomerular diseases. The test was able to identify disease-causing gene variants in 161 of 207 patients suspected of cystic disease, and 61 of 98 suspected of glomerular disease.

These high positive diagnostic rates can be explained by the fact that many of the patients included in this group had a family history of kidney diseases (56%), which increases the chances of inherited genetic illness.

Additionally, the targeted genetic analysis approach allowed for the detection of rare variations, such as altered copy number in both types of kidney disease, which accounted for 10% of the mutations detected in the 305 patients.

Alport syndrome was the most frequent molecular diagnosis among patients with suspected glomerular disease, accounting for 48% of cases. Half of the pediatric patients were found to have X-linked disease — mutations in the COL4A5 gene — and adult patients were mainly carriers of COL4A3 or COL4A4 gene mutations linked to autosomal dominant Alport syndrome (ADAS).

Of all the genetically diagnosed patients, 15% (34 of 222) were referred with an unspecified clinical diagnosis, and 2% (4 of 222) were found to have an inaccurate clinical diagnosis. This demonstrates that the 140-gene panel was able to provide crucial information to establish an accurate diagnosis in 17% of the patients.

This is particularly significant in the diagnosis of different cystic diseases in severe fetal cases detected by prenatal ultrasound screening, the researchers said. The team was able to provide a definitive diagnosis in 80% of the cases of prenatal presentation of cystic disease, which is important for providing precise genetic counseling to parents.

In addition to the fact that this diagnostic approach can effectively help identify patients with genetic kidney diseases, it can also significantly reduce costs. It is about 50-70% cheaper and covers a broader range of genetic abnormalities than standard genetic sequencing methods, the researchers said.

The team concluded that “massive parallel sequencing” of the kidney disease gene panel “is a comprehensive, non-invasive, efficient, and cost-effective tool for genetic diagnosis of cystic and glomerular inherited diseases.”

It can help identify “three-quarters of affected individuals, enabling a more precise estimation of the risk of progression of renal disease and risk of extra-renal manifestations,” they said.