Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3–5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling. We assembled what is to our knowledge the largest collection of data on the ability of four measurable characteristics of unaffected prospective parents to specify risk for autism among their offspring: (1) sub clinical autistic trait burden, (2) parental history of a sibling with ASD, (3) transmitted autosomal molecular genetic abnormalities, and (4) parental age. Leveraging phenotypic and genetic data in curated family cohorts, we evaluate the respective associations between these factors and child outcome when autism is present in the family in the parental generation. All four characteristics were associated with elevation in offspring risk; however, the magnitude of their predictive power—with the exception of isolated rare inherited pathogenic variants —does not yet reach a threshold that would typically be considered actionable for reproductive decision-making. Individual specification of risk to offspring of adults in ASD-affected families is not straightforwardly improved by ascertainment of parental phenotype, and it is not yet clear whether genomic screening of prospective parents in families affected by idiopathic ASD is warranted as a clinical standard. Systematic screening of affected family members for heritable pathogenic variants, including rare sex-linked mutations, will identify a subset of families with substantially elevated transmission risk. Polygenic risk scores are only weakly predictive at this time but steadily improving and ultimately may enable more robust prediction either singly or when combined with the risk variables examined in this study.

中文翻译：

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作为预防干预的遗传咨询：跨代自闭症风险的个体规范

尽管自闭症谱系障碍 (ASD) 是所有神经精神综合征中最容易遗传的疾病之一，但大多数受影响的孩子都是由未受影响的父母所生。最近，我们报告说，在大型流行病学家庭样本中，一级亲属患有 ASD 的成年人的后代患 ASD 的风险平均比一般人群增加 3-5%。下一个重要步骤是调查是否有可测量的个体父母将他们置于更高或更低复发风险的特征，因为这些信息可以允许更个性化的遗传咨询。我们收集了据我们所知最大的关于未受影响的准父母的四个可测量特征确定其后代自闭症风险的能力的数据集：（1）亚临床自闭症特征负担，(2) 患有 ASD 的兄弟姐妹的父母史，(3) 遗传的常染色体分子遗传异常，以及 (4) 父母年龄。利用精心策划的家庭队列中的表型和遗传数据，我们评估了当父母一代的家庭中存在自闭症时这些因素与儿童结局之间的各自关联。所有四个特征都与后代风险升高有关；然而，除了孤立的罕见遗传致病变异外，它们的预测能力的大小尚未达到通常被认为可用于生殖决策的阈值。确定父母表型并不能直接改善受 ASD 影响家庭中成人后代的个体风险，目前尚不清楚是否有必要对受特发性 ASD 影响的家庭中的准父母进行基因组筛查作为临床标准。对受影响的家庭成员进行系统筛查，以寻找可遗传的致病变异，包括罕见的性相关突变，将识别出传播风险显着升高的家庭子集。多基因风险评分目前仅具有较弱的预测能力，但在稳步提高，最终可能单独或与本研究中检查的风险变量结合时实现更稳健的预测。