Autism risk in offspring can be assessed through quantification of male sperm mosaicism

Martin W. Breuss, Danny Antaki, Renee D. George, Morgan Kleiber, Kiely N. James, Laurel L. Ball, Oanh Hong, Ileena Mitra, Xiaoxu Yang, Sara A. Wirth, Jing Gu, Camila A.B. Garcia, Madhusudan Gujral, William M. Brandler, Damir Musaev, An Nguyen, Jennifer McEvoy-Venneri, Renatta Knox, Evan Sticca, Martha Cristina Cancino BotelloJaviera Uribe Fenner, Maria Cárcel Pérez, Maria Arranz, Andrea B. Moffitt, Zihua Wang, Amaia Hervás, Orrin Devinsky, Melissa Gymrek, Jonathan Sebat, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father’s sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.

Original languageEnglish
Pages (from-to)143-150
Number of pages8
JournalNature medicine
Issue number1
StatePublished - Jan 1 2020


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