Exome Sequencing Reveals Genetic Origins of Some Kidney Disease Cases

Exome sequencing of patients with kidney disease and their families identified 17 different monogenetic causes of kidney disease.

A new study is raising the hope that genetic testing might help clinicians better understand the etiology of end-stage renal disease (ESRD), knowledge that could help improve transplantation outcomes.

The study was published in the journal NPJ Genomic Medicine. Corresponding author Jiancheng Guo, PhD, of Zhengzhou University, in Chian, and colleagues explained that chronic kidney disease already affects 850 million people around the world, and its numbers are expected to rise.

In about 3 in 10 cases, patients with chronic kidney disease also have family members with the disease, suggesting a possible genetic cause. Of those patients who progress to ESRD, about 15% do not have a primary renal diagnosis. In such cases, the origins of their disease are considered “unknown.”

Guo and colleagues said recent developments in genetic testing have made it possible to better understand the potential genetic underpinnings of many such cases. However, they said existing literature is sparse. To fix that, Guo and colleagues constructed a study using exome sequencing to search for genetic factors associated with chronic kidney disease in individual patients and in families.

“We hypothesize that genetic causes in adults are underrecognized, particularly in patients with a positive family history or patient cohorts with unknown etiology,” they wrote. “Improving the diagnosis of primary disease in patients with ESRD can therefore have implications for adequate clinical decisions for kidney transplantation.”

Guo and colleagues recruited 226 adult patients awaiting kidney transplants and 115 families to enroll in the trial between 2017 and 2019. Families that had multiple members affected by nephropathy or suspected kidney disease underwent Trio exome sequencing. The analysis yielded significant patterns.

Molecular genetic diagnoses were identified in just over half of the families (62) with suspected kidney disease. Of those 11.3% had autosomal recessive disease, 15.7% had an autosomal dominant disease, and 27.0% had an X-linked dominant disease.

Guo and colleagues found 17 different monogenic causes of kidney disease. Those genetic disorders confirmed the diagnosis in 33 families, resulted in modified or reclassified clinical diagnoses in 27 families, and established a diagnosis in 2 families that had ESRD of unknown etiology.

The investigators said improved diagnostic precision can have a number of important benefits for families and patients. They demonstrated that reverse phenotyping can correct wrong diagnoses, and genetic testing can also help diagnose and mitigate rare diseases that might affect the success of transplantation or help physicians better calculate individual patient risk.

“A timely diagnosis of certain rare disease, such as Fabry disease and mitochondrial disease identified in our study, is paramount for patient care,” they wrote. “As is known, enzyme replacement therapy is considered safe after kidney transplantation, and protective in terms of graft and patient survival, continuing even after the transplant to carry out a protective action on the extrarenal aspects of the disease.”

More broadly, the new findings show that a significant proportion of ESRD cases appear to be genetic in origin, though the authors said their study had the limitation of involving a relatively small and homogeneous study population.

“More genetic work and long-term follow-up in a larger cohort could fully evaluate the benefit of genetic analysis before renal transplantation,” they said.


Wang Z, Xu H, Xiang T, et al. An accessible insight into genetic findings for transplantation recipients with suspected genetic kidney disease. NPJ Genom Med. Published online July 2, 2021. doi:10.1038/s41525-021-00219-3