Autism risk in offspring can be assessed through quantification of male sperm mosaicism.,Nature Medicine

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Autism risk in offspring can be assessed through quantification of male sperm mosaicism.
Nature Medicine ( IF 58.7 ) Pub Date : 2019-12-23 , DOI: 10.1038/s41591-019-0711-0
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 Botello ₁₀ , Javiera Uribe Fenner ₁₀ , Maria Cárcel Pérez ₁₁ , Maria Arranz ₁₁ , Andrea B Moffitt ₁₂ , Zihua Wang ₁₂ , Amaia Hervás ₁₃ , Orrin Devinsky ₁₄ , Melissa Gymrek _{7,

8} , Jonathan Sebat _{3,

4,

5,

6} , Joseph G Gleeson _{1,

2}

Affiliation

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.

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.

中文翻译：

后代自闭症风险可以通过男性精子嵌合体的量化来评估。

父亲染色体上产生的从头突变对自闭症风险影响最大，并且与父亲受孕时的年龄相关。自闭症谱系障碍的复发风险很大，导致许多家庭拒绝未来怀孕，但评估父母性腺嵌合体的潜在影响尚未被考虑。我们使用深度全基因组测序测量了精子嵌合现象，了解后代中存在且仅在父亲精子中明显的变异，并鉴定了单核苷酸、结构和短串联重复变异。我们发现，镶嵌量化可以将由新突变引起的自闭症谱系障碍复发风险分层为绝大多数复发率接近 0% 和一小部分具有明显更高且可量化的风险，并且我们识别了有传播风险的新镶嵌变体未来的后代。因此，这表明遗传咨询将受益于精子嵌合体评估的增加。

更新日期：2019-12-23

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