Autism risk in offspring can be assessed through quantification of male sperm mosaicism
Autism risk in offspring can be assessed through quantification of male sperm mosaicism
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DOI：
10.1038/s41591-019-0711-0
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发表时间：
2020-01-01
期刊：
影响因子：
82.9
通讯作者：
Gleeson, Joseph G.
中科院分区：
文献类型：
--
作者：
Breuss, Martin W.;Antaki, Danny;Gleeson, Joseph G.
父亲染色体上的新生突变对自闭症风险的贡献最大，并与父亲受孕时的年龄相关。自闭症谱系障碍的复发风险是巨大的，导致许多家庭减少未来的怀孕，但评估父母性腺镶嵌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镶嵌性，对于存在于后代中的变体和仅在父亲精子中明显的变体，并鉴定了单核苷酸，结构和短串联重复变体。我们发现，镶嵌量化可以将自闭症谱系障碍的复发风险分层，由于从头突变，绝大多数复发率接近0%，一小部分复发率高得多，可量化的风险，我们确定了新的镶嵌变异，有传播给未来后代的风险。因此，这表明，遗传咨询将受益于精子镶嵌评估。对患有自闭症的孩子的家庭的父亲精子的遗传分析表明，对大多数夫妇来说，将疾病相关的新生突变传播给未来后代的复发风险接近0%，但对一小部分夫妇来说，这一风险要高得多。
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.