Vall d’Hebron and the University Hospital of Santa Maria in Lleida identify several cases of a rare disease transmitted by a sperm donor

Professionals from the Vall d’Hebron Research Institute (VHIR) and the Vall d’Hebron University Hospital, in collaboration with the Allergology Department of the University Hospital of Santa Maria de Lleida and the Biomedical Research Institute of Lleida (IRBLleida), have described the first documented case worldwide of transmission of hereditary angioedema associated with the F12 gene through an anonymous sperm donor.

The study, published in the scientific journal Frontiers in Immunology, reports the identification of several individuals carrying the same genetic variant, all conceived through assisted reproduction techniques using semen from a single donor.

The research began with the case of a patient who experienced recurrent episodes of swelling (angioedema) affecting the face and other parts of the body with no apparent cause and no response to standard anti-allergic treatments. Tests ruled out an allergic origin and pointed to a rare form of hereditary angioedema. Genetic analysis identified the T328K variant in the F12 gene, associated with a bradykinin-mediated form of the disease. This variant is recurrent and causes the disease in almost 100% of hereditary angioedema cases associated with F12.

During the subsequent study, the same variant was detected in other individuals conceived using semen from the same donor, while it was not present in the maternal lineage analysed. This finding suggested that the mutation might originate from the donor.

Researchers contacted the relevant fertility clinic, which coordinated the study with the sperm bank. Genetic testing confirmed that the donor was a heterozygous carrier of the T328K variant in the F12 gene.

Following this confirmation, the clinic initiated a notification process for the women who had used semen from this donor.

This procedure made it possible to identify additional carriers of the same genetic variant, some of whom currently show no clinical manifestations.

“From a genetic perspective, this case is particularly relevant because it demonstrates how a pathogenic variant can go unnoticed in an asymptomatic donor and be transmitted to several descendants”, explains Dr. Roger Colobran, head of the Translational Immunology Group at VHIR.

A rare disease with sex-specific impact

Hereditary angioedema is a rare genetic disease that causes recurrent episodes of swelling affecting the skin, the digestive tract or the airways. In some cases, it can become potentially severe.

It is a dominant genetic disorder; therefore, having only one affected copy of the gene is enough to develop the disease. However, it shows incomplete penetrance and variable expressivity, meaning that the onset and severity of symptoms vary among carriers of the mutation.

The form associated with the F12 gene has a particular feature: it affects men and women differently. In male carriers, the probability of developing symptoms is very low, whereas in female carriers it may reach 60–80%, often influenced by hormonal factors. This makes it possible for completely asymptomatic men to transmit the genetic variant without being aware of it.

“For clinicians, it is important to consider this disease when a patient presents recurrent swelling episodes that do not respond to conventional anti-allergic treatment, especially if there is a relationship with oestrogens, such as when taking oral contraceptives or during pregnancy”, highlights Dr. Mar Guilarte, consultant in the Allergology Department and coordinator of the Hereditary Angioedema Unit for children and adults (CSUR) at the Vall d’Hebron University Hospital and researcher in the Systemic Diseases Group at VHIR.

Implications for assisted reproduction

Researchers emphasise that this case highlights the challenges posed by dominant genetic diseases with incomplete penetrance in gamete donation programmes. Currently, genetic screening of donors mainly focuses on infectious diseases and some common recessive disorders.

According to the authors, the findings suggest that, in certain regions where this variant is more prevalent, targeted screening of the F12 gene could be considered.

The study was led by researchers Lluís Marquès, Laura Batlle-Masó, Eva Alcoceba, Sílvia Lara, Aina Aguiló, Johana Gil-Serrano, Mar Guilarte and Roger Colobran, from the University Hospital of Santa Maria, Vall d’Hebron University Hospital, Biomedical Research Institute of Lleida (IRBLleida) and the Vall d’Hebron Research Institute (VHIR).