TY - JOUR
T1 - Autism risk in offspring can be assessed through quantification of male sperm mosaicism
AU - Breuss, Martin W.
AU - Antaki, Danny
AU - George, Renee D.
AU - Kleiber, Morgan
AU - James, Kiely N.
AU - Ball, Laurel L.
AU - Hong, Oanh
AU - Mitra, Ileena
AU - Yang, Xiaoxu
AU - Wirth, Sara A.
AU - Gu, Jing
AU - Garcia, Camila A.B.
AU - Gujral, Madhusudan
AU - Brandler, William M.
AU - Musaev, Damir
AU - Nguyen, An
AU - McEvoy-Venneri, Jennifer
AU - Knox, Renatta
AU - Sticca, Evan
AU - Botello, Martha Cristina Cancino
AU - Uribe Fenner, Javiera
AU - Pérez, Maria Cárcel
AU - Arranz, Maria
AU - Moffitt, Andrea B.
AU - Wang, Zihua
AU - Hervás, Amaia
AU - Devinsky, Orrin
AU - Gymrek, Melissa
AU - Sebat, Jonathan
AU - Gleeson, Joseph G.
N1 - Funding Information:
We thank the participants in this study for their contribution. M.W.B. was supported by an EMBO Long-Term Fellowship (no. ALTF 174-2015), which is co-funded by the Marie Curie Actions of the European Commission (nos. LTFCOFUND2013 and GA-2013-609409), and an Erwin Schrödinger Fellowship by the Austrian Science Fund (no. J4197-B30). This study was supported by grants to J.G.G. from the NIH (nos. U01MH108898 and R01NS083823); the Simons Foundation Autism Research Initiative to J.G.G. (no. 571583), J.S. and M. Wigler (laboratory leader for A.B.M. and Z.W.); the NIH (nos. MH076431 and MH113715) to J.S.; and the Howard Hughes Medical Institute to J.G.G. Sequencing support was provided by the Rady Children’s Institute for Genomic Medicine and ONP. O.D. acknowledges support from the Silverman Family Foundation and Finding a Cure for Epilepsy (FACES) and Seizures. We thank B. Hamilton, N. Chi, V. Stanley, A. Marsh, M. Wigler and L. Alexandrov for suggestions. We thank R. Sinkovits, A. Majumdar, S. Strande and the San Diego Supercomputer Center for hosting the computing infrastructure necessary for completing this project.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077154044&partnerID=8YFLogxK
U2 - 10.1038/s41591-019-0711-0
DO - 10.1038/s41591-019-0711-0
M3 - Article
C2 - 31873310
AN - SCOPUS:85077154044
SN - 1078-8956
VL - 26
SP - 143
EP - 150
JO - Nature Medicine
JF - Nature Medicine
IS - 1
ER -