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

Martin W Breuss1,2, Danny Antaki3,4,5,6, Renee D George1,2, Morgan Kleiber3,4,5, Kiely N James1,2, Laurel L Ball1,2, Oanh Hong3,4,5,6, Ileena Mitra7,8, Xiaoxu Yang1,2, Sara A Wirth1,2, Jing Gu1,2, Camila A B Garcia1,2, Madhusudan Gujral3,4,5,6, William M Brandler3,4,5,6, Damir Musaev1,2, An Nguyen1,2, Jennifer McEvoy-Venneri1,2, Renatta Knox1,2,9, Evan Sticca1,2, Martha Cristina Cancino Botello10, Javiera Uribe Fenner10, Maria Cárcel Pérez11, Maria Arranz11, Andrea B Moffitt12, Zihua Wang12, Amaia Hervás13, Orrin Devinsky14, Melissa Gymrek7,8, Jonathan Sebat15,16,17,18, Joseph G Gleeson19,20

  1. Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.
  2. Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  3. Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA, USA.
  4. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
  5. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  6. Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
  7. Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  8. Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA.
  9. Department of Child Neurology, Weill Cornell Medical College, New York, NY, USA.
  10. Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain.
  11. Fundació Docència i Recerca Mútua Terrassa, Barcelona, Spain.
  12. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.
  13. Research Laboratory Unit, Fundació Docencia i Recerca Mútua Terrassa, Barcelona, Spain.
  14. Department of Neurology, Epilepsy Division, New York University School of Medicine, New York, NY, USA.
  15. Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA, USA. jsebat@ucsd.edu.
  16. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. jsebat@ucsd.edu.
  17. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. jsebat@ucsd.edu.
  18. Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. jsebat@ucsd.edu.
  19. Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA. jogleeson@ucsd.edu.
  20. Rady Children's Institute for Genomic Medicine, San Diego, CA, USA. jogleeson@ucsd.edu.

Abstract

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.

Presented By Martin Breuss

Genetics & Genome Biology, GenomicsNicholas Liao2020-01 (Jan)