A team from the Vall d’Hebron Research Institute (VHIR) has demonstrated the potential of a new genomic technology to improve the diagnosis of hereditary angioedema, a rare disease. Thanks to this tool, a previously undetectable genetic alteration has been identified in a family that had gone two decades without a genetic diagnosis. The study was led by the VHIR Translational Immunology Group in collaboration with the VHIR Systemic Diseases Group, the Immunology and Allergology Departments of Vall d’Hebron University Hospital, and the Radboud University Medical Center (Netherlands). The results have been published in the Journal of Clinical Immunology.

Hereditary angioedema affects approximately 1 in 50,000 people worldwide. It is characterised by recurrent episodes of swelling which, in the most severe cases, may lead to airway obstruction.

Most cases are caused by alterations in the SERPING1 gene, resulting in what is known as hereditary angioedema due to C1 inhibitor deficiency. Although several genetic techniques exist to identify these alterations, they have limitations, and 5–10% of patients still lack a confirmed genetic diagnosis.

The potential of optical genome mapping

This study shows how a novel genetic analysis technique, known as optical genome mapping (OGM), can help identify complex genetic alterations that may go unnoticed with conventional techniques such as standard sequencing.

This technique, previously used in other genetic diseases, enables the analysis of long DNA molecules labelled with fluorescent markers at specific sites. These images can be compared with the human reference genome map to identify differences. “We have shown that OGM is a useful tool for detecting structural alterations in the SERPING1 gene, such as insertions or deletions of DNA fragments. As these types of alterations are relatively common in this disease, this technique may be particularly useful when conventional methods fail to achieve a genetic diagnosis”, says Dr. Roger Colobran, head of the Translational Immunology group at VHIR.

A key finding in a family without a genetic diagnosis

The study has not only confirmed previously known alterations but has also identified new ones. Specifically, it describes for the first time a case in which the disease is caused by the insertion of a mobile element within the SERPING1 gene, altering its function. This finding was made in a family treated at Vall d’Hebron, with three affected generations who, despite having a clear clinical diagnosis, had lacked genetic confirmation for over 20 years.

Mobile elements are small DNA fragments capable of moving or copying themselves within the genome and are very difficult to detect. Some are ancient remnants of viruses that integrated into human DNA millions of years ago and remain as an evolutionary footprint. “OGM was key to detecting this insertion, but to identify exactly which mobile element it was and how it had integrated into the genome, we used a technique that reads long DNA fragments (LR-WGS). The combination of these tools has enabled us to precisely define an alteration that had not previously been detectable”, explains Dr. Laura Batlle-Masó, researcher in the Translational Immunology group at VHIR.

The study results indicate that combining new genomic technologies, such as optical genome mapping and long-read DNA sequencing, can significantly improve the diagnosis of rare diseases.

“These findings help explain why some patients with a clear clinical diagnosis still lack an identified genetic cause. Integrating these new tools opens the door to solving cases that have so far remained unresolved and to advancing towards more personalised medicine”, explains Dr. Mar Guilarte, specialist in the Allergology Department and coordinator of the Hereditary Angioedema Unit for children and adults (CSUR) at Vall d’Hebron University Hospital, and researcher in the Systemic Diseases group at VHIR.

Although this technique is not yet routinely available in hospitals, researchers suggest it could be implemented in the near future and be useful not only for hereditary angioedema but also for many other genetic diseases.

This research was funded by the Instituto de Salud Carlos III through project PI23/00161, co-funded by the European Regional Development Fund (ERDF). Part of this work was carried out within the Solve-RD consortium and supported by the European Reference Network on Rare Immunological, Autoinflammatory and Autoimmune Diseases (ERN-RITA). Dr. Laura Batlle-Masó holds a “Sara Borrell” postdoctoral fellowship (CD24/00011) from the Instituto de Salud Carlos III.