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

August 6, 2020 Nicholas Liao

Nat Med. 2020 Jan;26(1):143-150. doi: 10.1038/s41591-019-0711-0. | PubMed

Martin W Breuss^1,², Danny Antaki^3,^4,^5,⁶, Renee D George^1,², Morgan Kleiber^3,^4,⁵, Kiely N James^1,², Laurel L Ball^1,², Oanh Hong^3,^4,^5,⁶, Ileena Mitra^7,⁸, Xiaoxu Yang^1,², Sara A Wirth^1,², Jing Gu^1,², Camila A B Garcia^1,², Madhusudan Gujral^3,^4,^5,⁶, William M Brandler^3,^4,^5,⁶, Damir Musaev^1,², An Nguyen^1,², Jennifer McEvoy-Venneri^1,², Renatta Knox^1,^2,⁹, Evan Sticca^1,², Martha Cristina Cancino Botello¹⁰, Javiera Uribe Fenner¹⁰, Maria Cárcel Pérez¹¹, Maria Arranz¹¹, Andrea B Moffitt¹², Zihua Wang¹², Amaia Hervás¹³, Orrin Devinsky¹⁴, Melissa Gymrek^7,⁸, Jonathan Sebat^15,^16,^17,¹⁸, Joseph G Gleeson^19,²⁰

Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.
Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA, USA.
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA.
Department of Child Neurology, Weill Cornell Medical College, New York, NY, USA.
Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain.
Fundació Docència i Recerca Mútua Terrassa, Barcelona, Spain.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.
Research Laboratory Unit, Fundació Docencia i Recerca Mútua Terrassa, Barcelona, Spain.
Department of Neurology, Epilepsy Division, New York University School of Medicine, New York, NY, USA.
Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA, USA. jsebat@ucsd.edu.
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. jsebat@ucsd.edu.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA. jsebat@ucsd.edu.
Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. jsebat@ucsd.edu.
Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA. jogleeson@ucsd.edu.
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