Autosomal dominant transmission reframes reproductive counseling in Myhre syndrome: a novel family and literature review

Journal article

Myhre syndrome is a rare disorder that typically results from a de novo SMAD4 variant. De novo SMAD4 variants have recently been shown to be associated with ‘selfish selection’ in the male germline, explaining their exclusive paternal origin and the paternal age effect reported for Myhre syndrome. Over recent years, there has been a steady increase in the number of families reported with an affected parent and child. We expand the literature of families with Myhre syndrome reporting a mildly affected 38-year-old mother and her 4-year-old son who carry the SMAD4 p.Arg496Cys variant, consistent with all other reports of inherited Myhre syndrome. To better delineate the phenotypic spectrum, we developed a clinical severity score and compared familial cases to sporadic cases, revealing a milder phenotype in familial cases. Affected mothers with Myhre syndrome may be at increased risk of infertility and pregnancy loss. Since identification of the mode of transmission is essential for accurate reproductive counseling and appropriate clinical surveillance, we propose a nuanced reproductive and genetic counseling strategy that emphasizes awareness of potential autosomal dominant transmission, paternal age-related risk, and obstetric complications.

Authors: Brand, MR; Vanbelleghem, E; Kay, AC; Goriely, A; Demir, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: American Journal of Medical Genetics Part C: Seminars in Medical Genetics
• Place of publication: United States
• Publication date: 2025-12-07
• Acceptance date: 2025-11-04
• DOI: 10.1002/ajmg.c.32161
• EISSN: 1552-4876
• ISSN: 1552-4868
• Pmid: 41355326
• Language: English
• Keywords: de novo variants; Myhre syndrome; paternal age-effect; recurrence risk; reproductive genetic counseling; selfish spermatogonial selection