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

The index case was an 18-year-old woman with recurrent estrogen-dependent angioedema who was identified as a heterozygous carrier of the F12 T328K variant.

• The patient presented with recurrent episodes of angioedema with normal C1-inhibitor levels and function.
• She had poor response to conventional antiallergic therapy.
• Molecular analysis identified the heterozygous F12 c.983C>A/p.Thr328Lys (T328K) variant.
• The clinical presentation was described as estrogen-dependent, consistent with the known sex-dependent expression of HAE-FXII.

The index case's asymptomatic twin brother also carried the heterozygous F12 T328K variant, while their mother tested negative, strongly suggesting paternal transmission via sperm donation.

• Familial investigation revealed the same F12 T328K variant in the twin brother, who was asymptomatic.
• The mother tested negative for the variant.
• The absence of the variant in the mother and its presence in both siblings strongly implicated the sperm donor as the source.
• This pattern is consistent with the known incomplete penetrance and sex-dependent clinical expression of HAE-FXII, where males may remain asymptomatic.

Genetic testing confirmed that the sperm donor was a heterozygous carrier of the F12 T328K variant, representing the first documented transmission of HAE-FXII through sperm donation.

• The fertility clinic was contacted following identification of the likely paternal transmission.
• Genetic testing of the sperm donor confirmed heterozygous carrier status for the F12 T328K variant.
• The donor was presumed to be asymptomatic, consistent with the incomplete penetrance and sex-dependent expression of HAE-FXII.
• Women who had conceived using this donor's sperm were subsequently notified.

A second unrelated family was identified through the donor notification process, in which a young woman also carried the heterozygous F12 T328K variant.

• The second affected individual was identified after notification of women who had conceived using the same sperm donor.
• This young woman was found to carry the heterozygous F12 T328K variant.
• At the time of reporting, she was asymptomatic and under specialist follow-up.
• This finding demonstrates the potential for a single donor to transmit an autosomal dominant variant to multiple unrelated offspring.

HAE-FXII is a rare autosomal dominant disorder characterized by incomplete penetrance and marked sex-dependent clinical expression, with most affected individuals carrying the recurrent F12 c.983C>A/p.Thr328Lys (T328K) founder variant.

• The condition is mediated by bradykinin and presents with recurrent episodes of angioedema.
• The T328K variant is described as a recurrent founder variant.
• Incomplete penetrance means carriers may remain clinically silent, as observed in the asymptomatic male donor and twin brother.
• Sex-dependent penetrance means female carriers, particularly those exposed to estrogen, are more likely to develop clinical symptoms.

The authors recommend consideration of targeted screening for recurrent pathogenic variants such as F12 T328K in sperm donors in regions where HAE-FXII is more prevalent.

• Current findings highlight a gap in donor screening policies for autosomal dominant disorders with incomplete penetrance.
• The authors note important implications for genetic counseling and donor notification strategies.
• Targeted screening for the F12 T328K founder variant is proposed as a practical measure given its recurrent nature.
• The recommendation is geographically targeted to regions where HAE-FXII is more prevalent.