Developmental Variability in Autism Across 17 000 Autistic Individuals and 4000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis.
Developmental Variability in Autism Across 17 000 Autistic Individuals and 4000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis.
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DOI：
10.1001/jamapediatrics.2022.2423
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发表时间：
2022-09-01
期刊：
影响因子：
26.1
通讯作者：
Robinson, Elise B.
中科院分区：
文献类型：
--
作者：
Kuo, Susan S.;van der Merwe, Celia;Fu, Jack M.;Carey, Caitlin E.;Talkowski, Michael E.;Bishop, Somer L.;Robinson, Elise B.
这项研究描述了自闭症个体与未患自闭症的兄弟姐妹相比，在达到关键发育里程碑的年龄上的差异。自闭症患者平均在什么时候达到关键的发展里程碑？在这项横断面研究中，使用回顾性的、父母报告的来自17098名自闭症患者的数据，发现了平均发育里程碑获得的实质性差异。同时发生智力障碍、与神经发育障碍相关的基因变异、早期自闭症诊断和参与老年自闭症队列会增加平均延迟，并且较晚的里程碑（如短语说话、肠道控制）的平均延迟也比较早的里程碑（如微笑、坐着）要大。这些发现表明，自闭症的发育里程碑进展在不同的条件下存在很大差异，包括智力残疾的存在、基因检测结果、诊断时间和研究队列成员。自闭症中发育迟缓的存在是公认的，但很少有研究表明在这一人群中发育里程碑的实现具有可变性。基于共同发生的智力残疾（ID）、与神经发育障碍（NDD）相关的罕见破坏性遗传变异、自闭症诊断年龄和研究队列成员，表征自闭症个体达到关键发育里程碑的年龄变异性。研究小组协调了来自4个自闭症横断面队列的数据：自闭症遗传学研究交流（n = 3284; 1997-2015），自闭症单纯性收集（n = 694; 2008-2011）， Simons单纯性收集（n = 2753; 2008-2011）和Simons基金会为自闭症研究提供知识（n = 10367； 2016-至今）。最后一个样本进一步包括了4145名没有自闭症诊断或ID的兄弟姐妹。方便样本为21 243名4至17岁的自闭症个体或其兄弟姐妹。父母报告了参与者达到关键里程碑的年龄，包括微笑、坐直、爬行、行走、用勺子喂食自己、说话、说短语，以及获得膀胱和肠道控制。研究人员对5295名自闭症患者及其亲生父母进行了遗传鉴定，以确定ndd相关基因的新生变异。研究小组进行了时间到事件的分析，以估计和比较自闭症个体、自闭症个体亚组和兄弟姐妹样本中达到里程碑的时间百分位数。1798名自闭症患者（平均年龄9.15岁，80.8%为男性）与4145名没有自闭症或ID的兄弟姐妹（平均年龄10.2岁，50.2%为女性）相比，表现出里程碑成就的延迟，中位（IQR）延迟从0.7（0.3-1.6）到19.7（11.4-32.2）个月不等。更严重和更多变的自闭症延迟与同时发生的ID、携带与ndd相关的罕见基因变异以及在5岁之前被诊断为自闭症有关。更严重和更可变的延迟也与早期研究队列的成员有关，这与过去30年来自闭症诊断和确定的扩展相一致。作为迄今为止对自闭症发育里程碑成就的最大总结，据我们所知，这项研究证明了不同条件下的实质性发育变异性，并为理解自闭症的表型和病因异质性提供了重要的背景。
This study characterizes variability in the age at which autistic individuals attain key developmental milestones compared with siblings who do not have an autism diagnosis. When do autistic individuals, on average, attain key developmental milestones? Using retrospective, parent-reported data from 17 098 autistic individuals in this cross-sectional study, a found substantial variability in average developmental milestone acquisition was found. Average delays increased with co-occurring intellectual disability, presence of a genetic variant associated with neurodevelopmental disorders, earlier autism diagnosis, and participation in older autism cohorts, and average delays also were larger for later milestones (eg, phrase speech, bowel control) than earlier milestones (eg, smiling, sitting). These findings show that developmental milestone progress in autism varies substantially under different conditions, including presence of intellectual disability, genetic testing results, diagnosis timing, and study cohort membership. Presence of developmental delays in autism is well established, yet few studies have characterized variability in developmental milestone attainment in this population. To characterize variability in the age at which autistic individuals attain key developmental milestones based on co-occurring intellectual disability (ID), presence of a rare disruptive genetic variant associated with neurodevelopmental disorders (NDD), age at autism diagnosis, and research cohort membership. The study team harmonized data from 4 cross-sectional autism cohorts: the Autism Genetics Research Exchange (n = 3284; 1997-2015), The Autism Simplex Collection (n = 694; 2008-2011), the Simons Simplex Collection (n = 2753; 2008-2011), and the Simons Foundation Powering Autism Research for Knowledge (n = 10 367; 2016-present). The last sample further included 4145 siblings without an autism diagnosis or ID. Convenience sample of 21 243 autistic individuals or their siblings without an autism diagnosis aged 4 to 17 years. Parents reported ages at which participants attained key milestones including smiling, sitting upright, crawling, walking, spoon-feeding self, speaking words, speaking phrases, and acquiring bladder and bowel control. A total of 5295 autistic individuals, and their biological parents, were genetically characterized to identify de novo variants in NDD-associated genes. The study team conducted time-to-event analyses to estimate and compare percentiles in time with milestone attainment across autistic individuals, subgroups of autistic individuals, and the sibling sample. Seventeen thousand ninety-eight autistic individuals (mean age, 9.15 years; 80.8% male) compared with 4145 siblings without autism or ID (mean age, 10.2 years; 50.2% female) showed delays in milestone attainment, with median (IQR) delays ranging from 0.7 (0.3-1.6) to 19.7 (11.4-32.2) months. More severe and more variable delays in autism were associated with the presence of co-occurring ID, carrying an NDD-associated rare genetic variant, and being diagnosed with autism by age 5 years. More severe and more variable delays were also associated with membership in earlier study cohorts, consistent with autism’s diagnostic and ascertainment expansion over the last 30 years. As the largest summary to date of developmental milestone attainment in autism, to our knowledge, this study demonstrates substantial developmental variability across different conditions and provides important context for understanding the phenotypic and etiological heterogeneity of autism.
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影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
8.2
作者：
Jones, Emily J. H.;Gliga, Teodora;Bedford, Rachael;Charman, Tony;Johnson, Mark H.
通讯作者：
Johnson, Mark H.
DOI：
10.1176/appi.ajp.2017.16101115
发表时间：
2017-06-01
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Bishop SL;Farmer C;Bal V;Robinson EB;Willsey AJ;Werling DM;Havdahl KA;Sanders SJ;Thurm A
通讯作者：
Thurm A
影响因子：
6.2
作者：
Klei L;McClain LL;Mahjani B;Panayidou K;De Rubeis S;Grahnat AS;Karlsson G;Lu Y;Melhem N;Xu X;Reichenberg A;Sandin S;Hultman CM;Buxbaum JD;Roeder K;Devlin B
通讯作者：
Devlin B
影响因子：
6.8
作者：
AKAIKE, H
通讯作者：
AKAIKE, H