A new method may give more patients with rare diagnoses a genetic explanation
Region Stockholm
Researchers at KTH and clinicians at Karolinska University Hospital are collaborating to improve genetic diagnostics for rare diseases. By gaining a deeper understanding of how the genome functions in healthy cells – and what happens when it is affected by disease – they hope to provide more patients with a reliable diagnosis.
So far, the multi‑year collaboration has led to several clear improvements in clinical diagnostics. The research project has now received renewed funding from KTH and Region Stockholm’s annual call “Health, Medicine and Technology” (HMT) to develop methods that can help more patients receive a diagnosis in a shorter time.
Many patients are investigated for suspected rare diagnoses that affect brain development, but despite today’s genetic tests, far from all receive a clear answer. In a joint research project, researchers and clinicians are developing new methods that can complement current investigations for rare diagnoses that may cause neurocognitive symptoms, such as ADHD and autism within the NPF spectrum. The aim is to enable more patients to receive a clear genetic diagnosis and an explanation of what in the genome causes their symptoms, so that healthcare can more quickly provide appropriate follow‑up.
A new dimension in diagnostics
Anna Lindstrand, senior consultant in clinical genetics at Karolinska University Hospital and professor at Karolinska Institutet, and Pelin Sahlén, lecturer in gene technology at KTH, have conducted research in the field for several years. The project has now received renewed funding from the HMT call to map the genome’s 3D structure using HiCap, a method developed by Pelin Sahlén and now being tested in clinical investigations.
“Some patients do not have a classic mutation in a gene; instead, the disease is caused by the genome being rearranged, where parts of the chromosomes have switched places. The genes may look normal on paper but still be regulated incorrectly. We study this by comparing the genome’s 3D structure in healthy individuals and patients. We want to understand how the misregulation affects the cells,” says Pelin Sahlén.
When the genome ‘changes places’
Today, only around 25 percent of those investigated for a suspected rare diagnosis in Region Stockholm receive a genetic diagnosis. According to Anna Lindstrand, there is still much to learn about the causes of these types of diseases, and the hope is to advance diagnostics.
“We hope that HiCap analyses can give us clues about where in the genome we should look using the analyses we perform today and help reduce unclear findings,” says Anna Lindstrand.
Pelin Sahlén adds:
“If I’m being realistic, I don’t think we will be able to diagnose everyone, but reaching 60–70 percent would be fantastic. The vision is to develop a method that can be used in clinical care so that more patients receive a diagnosis sooner.”
A diagnosis that makes a difference
With a clear genetic diagnosis, healthcare can also be more precise. Although targeted treatments exist only for a small portion of the estimated 7,000–10,000 rare diseases known today, new drugs and clinical trials are continuously being developed – but without a diagnosis, patients risk missing them.
A diagnosis can also help healthcare plan appropriate interventions and follow‑up. In some cases, it can also prevent unnecessary investigations. According to Anna Lindstrand, it is not only about precision treatment but also about precision care.
“Receiving a genetic diagnosis is important for understanding disease progression, but it also gives families answers about heredity and future risks,” she says.
How important is the collaboration between research and clinical practice?
“In this type of precision‑medicine research, shared leadership is needed – a clinical leader who understands the relevant questions and a technical leader who knows what the technology can deliver. That’s when we can truly find new answers,” says Anna Lindstrand.
So far, the multi‑year collaboration has led to several clear improvements in clinical diagnostics. The researchers have refined the analysis of whole‑genome sequencing data, enabling more patients to receive diagnoses and improving assessments. RNA analysis is already used in some investigations, and the researchers now aim to demonstrate when it can provide more reliable diagnoses in additional cases.
“If we succeed in using functional data, such as RNA analysis, to show what the genetic change actually does in the cell, it will have a major impact not only on neurodevelopmental conditions but also on rare diagnoses in general,” says Pelin Sahlén.
Text: Anna-Lena Ahlberg
Photo: Magnus Glans