Autism spectrum disorder (ASD) is a major health care issue, affecting 1 in 200 live births, with a male to female ratio of 4:1. In the last few years, important advances in deciphering the neurogenetic bases of ASD have been achieved. However, many patients still are not offered systematic investigations. In order to improve patients’ access to services, disseminate knowledge, and counteract the loss of opportunity to diagnose a genetic condition, an ambulatory team was established and has visited day-care hospitals across the Greater Paris region since 1998. The team offered comprehensive clinical genetics consultations and gradually improved genetics services to more than 500 patients with ASD in their respective institutions. While array comparative genomic hybridization (CGH) and screening for fragile X syndrome detected pathogenic variants in 10% of patients, further implementation of highthroughput sequencing of reported intellectual disability/ ASD genes identified pathogenic or likely pathogenic variants in 25% of investigated patients. Most variants occurred de novo (70%), but 30% were X-linked or recessively inherited and only 27 genes were found to be mutated. All diagnosed cases were syndromic forms of ASD, with moderate to severe intellectual disability. Some patients had undiagnosed early-onset, transient epilepsy, later ascribed to a genetic condition when deferred behavioral problems occurred. Overall, onsite medical genetics consultations identified previously undiagnosed genetic conditions in 35% of children and young adults with ASD. This diagnostic yield may be an underestimate, given that variants of uncertain significance and variants in strong candidate genes were not regarded as the cause of the disease. Based on this study, it seems mandatory to offer systematic array CGH and panel sequencing of known disease genes in syndromic/atypical individuals with ASD with an associated intellectual disability. Owing to costs and number of patients, decision makers may consider stepwise procedure, first screening a limited number of disease genes in a much larger number of patients, especially those with syndromic ASD and intellectual disability. In the future, current guidelines will hopefully mention genetics screening of the most frequent ASD genes as an explicit recommendation to professionals, which is not currently the case. While recognizing a genetic condition had no immediate impact on the case management, this information was often received by parents as a ‘relief’ that helped them overcome hardship and alleviate the sense of guilt and self-blame of having given birth to a child with ASD. Relating to support groups and other families facing similar situations was also appreciated, as it fostered studies aimed at delineating natural history and the long-term outcome of ASD subtypes. Conversely, genetics diagnosis had a significant impact on genetic counseling when de novo sequence or copy number pathogenic variants were identified, as they significantly reduced recurrence risk to parents and relatives. Omitting or postponing medical genetics consultations and failing to warn of potential genetic risks may have serious consequences in inherited forms of ASD. Since one-third of patients carry single, recognizable disease-causing variants, what about the other two-thirds of cases? Do they result from hitherto unknown genomic events, paucigenic interactions between susceptibility factors, or as yet unknown environmental factors? Future advances in functional brain imaging and whole genome sequencing will certainly shed some light on this ‘missing heritability’. On the other hand, while it is tempting (and popular) to consider epigenetic scenarios in ASD, experimental evidences supporting this hypothesis are obviously hampered by the current limitation in gaining access to the brain. Interestingly, population-based cohort studies already support the possible role of epigenetic factors in ASD, particularly in relation to assisted reproductive technology, preterm birth, cocaine consumption, and exposure to progesterone and valproate. In this respect, excluding single pathogenic variants will certainly contribute to improve detection of those weak, yet likely signals in ASD.

中文翻译：

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解开自闭症谱系障碍的病因复杂性

自闭症谱系障碍 (ASD) 是一个主要的医疗保健问题，每 200 名活产婴儿中就有 1 人受到影响，男女比例为 4:1。在过去几年中，在破译 ASD 的神经发生基础方面取得了重要进展。然而，许多患者仍然没有得到系统的调查。为了改善患者获得服务的机会、传播知识并抵消诊断遗传病的机会的丧失，自 1998 年以来，成立了一个门诊团队，并访问了大巴黎地区的日托医院。该团队提供了全面的临床遗传学咨询，逐步完善对所在机构 500 余名 ASD 患者的遗传学服务。虽然阵列比较基因组杂交 (CGH) 和脆性 X 综合征筛查在 10% 的患者中检测到致病变异，但对报告的智力障碍/ ASD 基因的高通量测序进一步实施在 25% 的受调查患者中发现了致病或可能的致病变异。大多数变异是从头发生的 (70%)，但 30% 是 X 连锁或隐性遗传的，只有 27 个基因被发现突变。所有确诊病例均为 ASD 综合征，伴有中度至重度智力障碍。一些患者有未确诊的早发性、短暂性癫痫，后来在出现延迟行为问题时将其归因于遗传病。总体而言，现场医学遗传学咨询确定了 35% 的患有 ASD 的儿童和年轻人以前未确诊的遗传病。考虑到意义不确定的变异和强候选基因的变异不被视为疾病的原因，这种诊断结果可能被低估了。根据这项研究，似乎必须对患有 ASD 并伴有相关智力障碍的综合征/非典型个体提供系统阵列 CGH 和已知疾病基因的面板测序。由于成本和患者数量的原因，决策者可能会考虑逐步程序，首先在大量患者中筛选有限数量的疾病基因，尤其是那些患有综合征性 ASD 和智力障碍的患者。将来，当前的指南有望将最常见的 ASD 基因的遗传学筛查作为对专业人士的明确建议，而目前情况并非如此。虽然认识到遗传病对病例管理没有直接影响，但父母经常收到这些信息作为“救济”，帮助他们克服困难并减轻因生下患有 ASD 的孩子而产生的内疚感和自责感. 与面临类似情况的支持团体和其他家庭的关系也受到赞赏，因为它促进了旨在描绘 ASD 亚型的自然史和长期结果的研究。相反，当发现新发序列或拷贝数致病变异时，遗传学诊断对遗传咨询有重大影响，因为它们显着降低了父母和亲属的复发风险。遗漏或推迟医学遗传学咨询以及未能警告潜在的遗传风险可能会对遗传性 ASD 产生严重后果。由于三分之一的患者携带单一的、可识别的致病变异，那么另外三分之二的病例呢？它们是由迄今为止未知的基因组事件、易感因素之间的少基因相互作用还是未知的环境因素引起的？功能性脑成像和全基因组测序的未来进展肯定会为这种“缺失的遗传性”提供一些启示。另一方面，虽然在 ASD 中考虑表观遗传场景很诱人（并且很受欢迎），但支持这一假设的实验证据显然受到当前进入大脑的限制的阻碍。有趣的是，基于人群的队列研究已经支持表观遗传因素在 ASD 中的可能作用，特别是与辅助生殖技术、早产、可卡因消费、以及接触黄体酮和丙戊酸盐。在这方面，排除单一致病变异肯定有助于改善对 ASD 中那些微弱但可能的信号的检测。