A family from Nottingham have finally received the correct diagnosis for a dangerous inherited heart condition - after more than three decades of uncertainty - thanks to advances in genetic testing.
Doctors had long believed the family was affected by Marfan syndrome, a condition that can weaken the body’s connective tissues and lead to serious heart problems. But new research has revealed the real cause: a rarer condition called Loeys-Dietz syndrome type 4.
The condition came to light after several family members developed dangerous swelling of the aorta, the main blood vessel carrying blood from the heart. In some cases, this led to life-threatening tears known as dissections.
One male relative in his 30s required major heart surgery after his aorta rapidly enlarged. Other relatives had similar issues over the years, reinforcing the belief that the family had Marfan syndrome.
But something didn’t quite fit.
The clue hidden in DNA
Despite decades of testing, doctors couldn’t find the genetic cause - until researchers revisited the family’s DNA using more advanced techniques.
A range of genomic tests between 1995 and 2015 failed to identify a pathogenic variant in the family.
But in 2015 the family took part in the UK 100,000 Genomes Project (opens in a new tab) - a groundbreaking UK government initiative which ran from 2012 to 2018 that sequenced 100,000 whole genomes from NHS patients with rare diseases and cancers. Managed by Genomics England, it aimed to integrate genomic medicine into routine healthcare, deliver personal diagnoses, and jumpstart the UK genomics industry.
The 100k Genomes Project created one of the world's largest clinical-genomic databases, leading to the creation of the NHS Genomic Medicine Service.
Genetic testing technology and knowledge at the time did not provide a diagnosis for the family, but since their genetic data was securely stored within the National Genomics Research Library, advances in both technology and our understanding of genetics enabled their genetic data to be revisited which led to doctors discovering a tiny missing piece of genetic material in a gene called TGFB2.
This small deletion had been missed by earlier tests, because the size was difficult to detect using standard methods at the time.
That missing fragment turned out to be the key, confirming the family actually had Loeys-Dietz syndrome type 4, not Marfan syndrome.
Although the two conditions look similar, getting the right diagnosis is critical.
Dr Abhijit Dixit, Consultant Clinical Geneticist at Nottingham University Hospital, who co-authored a recent paper on the family's diagnosis published in the American Journal of Medical Genetics, explains the significance for the family:
For this family, reanalysis of their genetic data identified five family members as carriers of the gene change, which means they will now receive regular heart scans. For eight other relatives, we were able to reassure them that they have not inherited the condition and no longer need ongoing monitoring.
Dr Abhijit Dixit, Consultant Clinical Geneticist at Nottingham University Hospital
Ending years of uncertainty
For years, many family members underwent repeated scans and lived with anxiety about whether they might develop serious heart problems.
The new diagnosis has brought clarity - and peace of mind.
Speaking on behalf of the family involved, Jilly from Nottingham said: “Getting this diagnosis has been a massive bonus to the family because it puts an end to the uncertainty. Several of our family members, including my daughter and a cousin of mine, have discovered that they are unaffected, so they no longer need to be monitored.
Before this the whole family was under surveillance and monitoring, but now we can identify which members of our family are affected, which is a huge relief, after so long not knowing.
Jilly from Nottingham, one of the family members
Researchers say this case highlights how re-analysing genetic data with improved technology can uncover diagnoses that were previously missed.
Small genetic changes like this are particularly difficult to detect but can have major consequences.
As genetic tools continue to improve, more families with unexplained inherited conditions could finally get answers - sometimes decades later.
A recent study looked at over four thousand people from over two thousand families who were early participants in the 100k Genomes Project. It found that using whole genome sequencing led to a new diagnosis for 25% of the participants. Of these new diagnoses, 14% found variations in regions of the genome that would be missed by other methods, including other types of non-whole genomic tests.