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New genetic analysis offers diagnosis for families with previously unexplained kidney failure

03 April 2024

In new results, published in the Genetics in Medicine Open, Professor John Sayer and his team at Newcastle University used a new method of analysing patients’ DNA and discovered that a missing gene was responsible for previously unexplained kidney failure.

Genetic causes of kidney disease

There are many reasons why a person might develop kidney failure, but in some cases, patients will never get a precise diagnosis. Understanding the genetic cause of kidney failure is important as it can open doors for personalised medicine, targeted treatment and better outcomes for patients.

With advances in technology, genome sequencing (analysing a person’s genetic makeup to search for changes in their DNA that might cause disease) is now common practice when investigating diseases that run in families. But it is not simple; the information requires sophisticated filtering and analysis to find the answers you are looking for. One particular challenge is identifying missing or duplicated sections of DNA.

Professor John Sayer sitting at his lab bench
Professor John Sayer

Approaching the data with fresh eyes

With funding from Kidney Research UK and the Northern Counties Kidney Research Fund, John and the team developed a new method of analysis and used it to study data from the Genomics England 100,000 Genomes Project - a project that sequenced the genomes of 100,000 individuals including people with rare diseases and cancer, as well as their family members.

Finding missing genes

The team analysed the genetic data of 959 patients with advanced kidney disease and found 11 patients who had a chunk of DNA missing that led to the complete loss of a kidney gene called NPHP1. The area in the genome that had this missing DNA was not picked up using the routine genetic analysis tools that are currently used, so these patients had previously been told that they had no genetic changes.

Although this condition can run in families, interestingly, the NPHP1 gene lies in a region of the genome that is also particularly susceptible to new genetic changes that appear for the first time in an individual rather than being passed down from their parents.

John said: “Our new genomic methods and their results have huge implications for the patients and families with kidney failure who were previously genetically unsolved. We are now able to give some patients a precise diagnosis, which allows their investigations, treatment and management to be tailored to their needs for the best possible outcomes.”

“We hope to provide a proper diagnosis for many more families in the future. This work is a reminder that it is always worth investigating the underlying reasons for kidney failure to get to the bottom of the condition.” Professor John Sayer

The team are now using cell lines to gain a deeper understanding of the disease process and to test potential new treatments.

Empowering patients with information

The Bingham family, from Hexham are part of the Genomics England 100,000 Genomes project and were one of the families identified as having the gene deletion, NPHP1-related kidney failure. They have three family members all affected by kidney disease: Noah and Ariel, who have both had kidney transplants, and their younger brother Casper. Mum Sarah has previously shared their story to raise awareness of the difficulties faced by families living with kidney disease and raised vital funds for research.

Selfie of family, mum, dad, two sones and one daughter
The Bingham family

Noah, who is now 23 years old, presented with kidney failure just after finishing his A levels. This was at the same time his younger sister Ariel was being treated for reduced kidney function. Both have received kidney transplants as their own kidney function reduced to dangerously low levels. The genetic results then allowed testing of their younger brother Casper, who also carried the genetic change and is being carefully monitored.

Mum Sarah said: “The genetic tests allowed Casper to receive his diagnosis before he was symptomatic. The knowledge that he will go into kidney failure and will need a transplant, though overwhelming at times, has meant we can arrange the support he needs and help him prepare for surgery and treatments well before they are necessary.”

“When nobody is able to explain why your children are ill, it is very unsettling, with no means of clarifying what might happen in the future. The diagnosis has meant that we have been able to prepare ourselves.”

Dr Aisling McMahon, executive director of research and policy at Kidney Research UK added: “This work from John and his team is a fantastic example of how new scientific insights can help to transform patient experiences of kidney disease and we are delighted to have played a part in it. We would like to thank the Bingham family for supporting this project, and wish them all well for the future.”

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