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. 2025 Dec 7.
doi: 10.1002/ajmg.c.32161. Online ahead of print.

Autosomal Dominant Transmission Reframes Reproductive Counseling in Myhre Syndrome: A Novel Family and Literature Review

Maggie R Brand  1 , Eva Vanbelleghem  2   3 , Alison C Kay  4   5   6 , Anne Goriely  4   5 , Senol Demir  7 , Peter J Hulick  8 , Breanne Prindeville  8 , Ashley W Wong  1 , Bert Callewaert  2   3 , Angela E Lin  1
Affiliations

Autosomal Dominant Transmission Reframes Reproductive Counseling in Myhre Syndrome: A Novel Family and Literature Review

Maggie R Brand et al. Am J Med Genet C Semin Med Genet. .

Abstract

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.

Keywords: De novo variants; Myhre syndrome; paternal age‐effect; recurrence risk; reproductive genetic counseling; selfish spermatogonial selection.

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References

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    1. Demir, S., C. Alavanda, G. Yesil, A. D. Aslanger, and E. A. Ates. 2023. “A Second Family With Myhre Syndrome Caused by the Same Recurrent SMAD4 Pathogenic Variation (p.Arg496Cys).” Molecular Syndromology 14, no. 2: 175–180. https://doi.org/10.1159/000527149.
    1. Goriely, A., and A. O. Wilkie. 2012. “Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences for Human Disease.” American Journal of Human Genetics 90, no. 2: 175–200. https://doi.org/10.1016/j.ajhg.2011.12.017.
    1. Kay, A. C., J. Wells, A. Goriely, and N. Hallowell. 2024. “Professionals' Views on Providing Personalized Recurrence Risks for de Novo Mutations: Implications for Genetic Counseling.” Journal of Genetic Counseling 34: 1–13. https://doi.org/10.1002/jgc4.1910.
    1. Lin, A. E., A. Alali, L. J. Starr, et al. 2024. “Corrigendum to “Gain‐Of Function Pathogenic Variants in SMAD4 Are Associated With Neoplasia in Myhre Syndrome”.” American Journal of Medical Genetics, Part A 194, no. 6: e63497. https://doi.org/10.1002/ajmg.a.63497.

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