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

• Published in: Nature medicine Vol. 26; no. 1; pp. 143 - 150
• Main Authors: Breuss, Martin W., Antaki, Danny, George, Renee D., Kleiber, Morgan, James, Kiely N., Ball, Laurel L., Hong, Oanh, Mitra, Ileena, Yang, Xiaoxu, Wirth, Sara A., Gu, Jing, Garcia, Camila A. B., Gujral, Madhusudan, Brandler, William M., Musaev, Damir, Nguyen, An, McEvoy-Venneri, Jennifer, Knox, Renatta, Sticca, Evan, Botello, Martha Cristina Cancino, Uribe Fenner, Javiera, Pérez, Maria Cárcel, Arranz, Maria, Moffitt, Andrea B., Wang, Zihua, Hervás, Amaia, Devinsky, Orrin, Gymrek, Melissa, Sebat, Jonathan, Gleeson, Joseph G.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2020; Nature Publishing Group
• Subjects: 631/114/2164; 631/208/2489/1512; 692/53/2423; Autism; Autistic Disorder - blood; Autistic Disorder - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromosomes; Complications and side effects; Disorders; Female; Gene sequencing; Genetic analysis; Genetic aspects; Genetic counseling; Genetic Predisposition to Disease; Genetic screening; Genomes; Health aspects; Humans; Infectious Diseases; Male; Metabolic Diseases; Molecular Medicine; Mosaicism; Mutation; Mutation - genetics; Neurosciences; Nucleotides; Offspring; Pedigree; Pervasive developmental disorders; Polymorphism, Single Nucleotide - genetics; Recurrence; Risk; Risk Factors; Sperm; Spermatozoa; Spermatozoa - metabolism; Whole genome sequencing; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-019-0711-0

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. Genetic analysis of paternal sperm from families with a child affected by autism reveals that the recurrent risk for transmitting disease-associated de novo mutations to future offspring is near 0% for most couples but is substantially higher for a small fraction of couples.