A medical mystery involving a young woman in Lleida has led to a world-first discovery. Researchers in Catalonia have traced a rare genetic disease back to a single, anonymous sperm donor who has passed the condition to at least three of his biological children.
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Through a groundbreaking investigation, a collaboration between the Vall d’Hebron University Hospital in Barcelona and the Hospital Universitari de Santa Maria in Lleida identified three individuals who inherited Hereditary Angioedema (HAE). This serious and uncommon disorder causes severe, unpredictable swelling beneath the skin. The findings, published in the scientific journal Frontiers in Immunology, highlight a new challenge for the world of assisted reproduction.
A Patient’s Search for Answers
The investigation began when an 18-year-old woman from Lleida sought medical help for a baffling series of sudden inflammatory episodes. She experienced recurrent angioedema, a deep swelling similar to hives, on her face and other parts of her body. According to reports in El País, the episodes had no apparent cause and did not respond to standard anti-allergic treatments like antihistamines and corticosteroids.
Doctors pursued a genetic cause following a severe episode, which involved swelling in her foot and subsequent throat tightness that restricted her breathing. Her medical history revealed a crucial clue: her symptoms first appeared weeks after she started taking oral contraceptives containing oestrogen. The symptoms later vanished when she paused the medication during the Covid-19 pandemic lockdown, only to reappear within days of resuming it.
This link to oestrogen, a known trigger for this specific type of HAE, prompted a genetic analysis. The tests confirmed she carried the T328K variant of the F12 gene, which is responsible for a form of Hereditary Angioedema. Lleida has also seen other unusual health reports, including a rare case of human swine flu detected in a farm worker last year.
Tracing the Genetic Trail
To confirm the origin of the gene, doctors conducted a family study. The patient’s mother tested negative for the variant. However, doctors found her brother, conceived using sperm from the same anonymous donor, was also a carrier. This confirmed they inherited the genetic variant from their biological father. While his sister’s symptoms were severe, her brother had experienced only a single, mild episode of lip swelling, highlighting the disease’s variable nature.
Researchers then contacted the fertility clinic where the siblings were conceived. The Vall d’Hebron Research Institute (VHIR) confirmed in a statement that the sperm bank tested the donor, finding he was a heterozygous carrier. This means he possessed one normal and one mutated copy of the F12 gene. Because he was asymptomatic, the condition went entirely undetected during the standard screening process.
“From a genetic point of view, this case is especially relevant because it demonstrates how a pathogenic variant can go unnoticed in an asymptomatic donor and be transmitted to several descendants,” said Dr. Roger Colobran, head of the Translational Immunology group at VHIR.
Implications for Donor Screening
Hereditary Angioedema is a dominant disorder, meaning a child has a 50% chance of inheriting it if one parent is a carrier. The condition disproportionately affects women, with up to 80% of female carriers developing symptoms, often triggered by hormonal changes or oestrogen-based medications. In contrast, male carriers like the donor are frequently asymptomatic or experience such mild symptoms they go undiagnosed.
Following the discovery, the fertility clinic notified all other women who had used sperm from the same donor. Several months later, another mother contacted Vall d’Hebron. Her 21-year-old daughter, also conceived with the donor’s sperm, tested positive for the genetic variant. She is the third confirmed case, and while currently asymptomatic, she is now under medical observation.
Researchers noted in their study that for confidentiality reasons, they do not know the total number of children conceived from this donor, but it is statistically probable that half of them are carriers. The case raises significant questions about genetic screening protocols for sperm and egg donors, particularly for dominant genetic conditions that may not manifest any symptoms in the donor themselves.
