# Transmission of F12-related hereditary angioedema through a sperm donor

## TL;DR

A rare genetic disorder causing angioedema was transmitted through a sperm donor, highlighting the need for genetic screening in assisted reproduction.

## Contribution

First documented case of HAE-FXII transmission via sperm donation, revealing implications for donor screening and counseling.

## Key findings

- HAE-FXII was transmitted through a sperm donor carrying the F12 T328K variant.
- Two unrelated families were identified with the same variant, showing asymptomatic carriers.
- The findings emphasize the importance of donor screening for autosomal dominant disorders.

## Abstract

Hereditary angioedema due to F12 pathogenic variants (HAE-FXII) is a rare autosomal dominant disorder characterized by recurrent episodes of angioedema mediated by bradykinin, incomplete penetrance, and marked sex-dependent clinical expression. Most affected individuals carry the recurrent F12 c.983C>A/p.Thr328Lys (T328K) founder variant. Here, we report the first documented transmission of HAE-FXII through sperm donation. The index case was an 18-year-old woman with recurrent estrogen-dependent angioedema, normal C1-inhibitor levels and function, and poor response to conventional antiallergic therapy. Molecular analysis identified the heterozygous F12 T328K variant. Familial investigation revealed the same variant in her asymptomatic twin brother, while their mother tested negative, strongly suggesting paternal transmission. The fertility clinic was contacted, and genetic testing confirmed that the sperm donor was a heterozygous carrier of the F12 T328K variant. Women who had conceived using this donor’s sperm were subsequently notified. Through this process, a second unrelated family was identified, in which a young woman was also found to carry the heterozygous F12 T328K variant and is currently asymptomatic under specialist follow-up. This study provides the first direct evidence of transmission of HAE-FXII through assisted reproductive technologies. Our findings highlight how autosomal dominant disorders with incomplete and sex-dependent penetrance can remain clinically silent in donors and be unknowingly transmitted to multiple offspring. These observations have important implications for genetic counseling, donor notification strategies, and donor screening policies, and support consideration of targeted screening for recurrent pathogenic variants such as F12 T328K in regions where HAE-FXII is more prevalent.