Elusive genetic changes discovered that could explain unsolved cases of Marfan Syndrome

New research has identified 20 genetic changes in a gene known to cause Marfan syndrome that could help to explain unsolved cases of the condition and enable more patients with the condition to receive a genetic diagnosis.

Rare genetic alterations to the FBN1 gene are known to be linked to Marfan syndrome - a connective tissue disorder that can have a ranging severity of symptoms, usually affecting the skeleton, eyes, or heart. It is one of the most common connective tissue disorders, affecting around 1 in 5,000 people in the UK. Diagnosing Marfan syndrome can be difficult as the symptoms can vary significantly from person to person and do not always develop during childhood. The most serious consequences of this condition are “aortic aneurisms”, bulges in the upper aorta, the body's main artery. These bulges can result in the aortic wall becoming weaker and individuals are prone to sudden aortic rupture, which can be life-threatening.

The research, led by Dr Alistair Pagnamenta from the University of Exeter and published in Genetics in Medicine, analysed genomic data from over 600 families with aortic aneurisms from the 100,000 Genomes Project to find out how unusual changes in the FBN1 gene affect Marfan syndrome. The research found 20 genetic changes in 23 of the families involved from all over the UK. These changes likely impact how the gene’s instructions are spliced together. This information helps to address how rare changes within typically unstudied regions of the gene might provide new diagnoses for patients.

All the 20 changes discovered were in the non-coding part of the gene. This part of the gene doesn’t code for protein and is underexplored in both research and clinical settings. As a result, many of these genetic variants were missed by conventional testing. In parallel with previous studies using FBN1 data from the 100,000 Genomes Project, this work helps demonstrate the benefits that whole genome sequencing can bring.

Like many with rare conditions, nearly all these families in which the new genetic changes were found had experienced diagnostic odysseys – waiting years for a diagnosis and answers. Steve Fisher was one of those who joined the 100,000 Genomes Project, and over a decade later received a formal and genetic diagnosis of Marfan syndrome for the first time when he was 71 years old. He had long suspected that he had the condition but was frequently told by doctors that he didn’t.

Steve said: “Being diagnosed with Marfan syndrome gave me closure on something I had been wondering about for decades. I was grateful to know a cause of some of the challenges and issues I had when I was growing up, but also proud that I hadn’t let it affect how I lived my life.

“Research like this that finds new routes towards more people getting diagnoses is fantastic. It means people can actively try and prevent some of the most dangerous complications of Marfan syndrome, like aortic dissection, which happened to me. I was very lucky to survive. There will be lots of people with the condition for whom frequent scans and monitoring could be potentially lifesaving.”