孤独症对于遗传学家而言一直是个未解之谜。科学家们一直在寻找与这种疾病有关的基因，他们发现，大约有10%的孤独症可能与遗传有关。如今，一个研究小组向着搞清另外90%孤独症患者——即所谓的散发病例——的致病原因迈出了新的一步。
由美国纽约州冷泉港实验室的Jonathan Sebat领导的研究小组，对来自264个家庭的脱氧核糖核酸（DNA）进行了研究。利用一系列相关技术，研究人员分析了导致复制数字变异的遗传物质——复制数字变异是指复制过程中丢失或得到相对较长的DNA片段。Sebat和同事发现，在参与这项研究的196名非孤独症患者中，只有约1%的人具有这一遗传缺陷，而在112名孤独症患者当中，这一比例却是前者的10倍（这些人都是家庭中唯一的孤独症患者）。与此相反的是，在47个显然通过遗传患上孤独症且有多名患者的家庭中，出现复制数字变异的比例却高达2%。研究小组在3月16日出版的美国《科学》杂志上报告了这一研究成果。研究人员在对那些只有一个孤独症患者的家庭进行了更为深入的研究后发现，这些患者的父母并没有携带遗传变异，这意味着这种疾病并非来自于遗传，但有可能源于母亲的卵子或父亲的精子。
Sebat推断，至少15%的孤独症病例以及相关的疾病与这种基因变异有关。他希望随着研究小组利用更灵敏的DNA探针对更多的家庭进行研究，能够搞清更多的相关细节，同时确定导致这种疾病的基因。Sebat表示：“随着采样范围和分析工作的不断增加，我们将对这种疾病的致病原理有一个更好的认识。”
与此同时，这一发现将为那些孤独症患者的父母提供帮助——这些父母通常担心这种疾病会在家族中遗传，并且导致今后生育的孩子也患上孤独症。美国新泽西州Rutgers大学的Linda Brzustowicz指出：“如果能够确定这种疾病是由于自发的染色体缺失所导致，那么家族中重复发病的可能性将大为降低。”
部分英文原文：
Published Online March 15, 2007
Science DOI: 10.1126/science.1138659
Science Express Index
Submitted on December 11, 2006
Accepted on March 6, 2007
Strong Association of De Novo Copy Number Mutations with Autism
Jonathan Sebat 1*, B. Lakshmi 1, Dheeraj Malhotra 1, Jennifer Troge 1, Christa Lese-Martin 2, Tom Walsh 3, Boris Yamrom 1, Boris Yamrom 1, Seungtai Yoon 1, Alex Krasnitz 1, Jude Kendall 1, Anthony Leotta 1, Deepa Pai 1, Ray Zhang 1, Yoon-Ha Lee 1, James Hicks 1, Sarah J. Spence 4, Annette T. Lee 5, Kaija Puura 6, Terho Lehtimäki 7, David Ledbetter 7, Peter K. Gregersen 5, Joel Bregman 8, James S. Sutcliffe 9, Vaidehi Jobanputra 10, Wendy Chung 10, Dorothy Warburton 10, Mary-Claire King 3, David Skuse 11, Daniel H. Geschwind 12, T. Conrad Gilliam 13, Kenny Ye 14, Michael Wigler 1*
1 Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
2 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
3 Department of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195-7720, USA.
4 Pediatrics and Neurodevelopmental Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1255, USA.
5 Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA.
6 Department of Child Psychiatry, University of Tampere, Medical School, Tampere, Finland.
7 Department of Clinical Chemistry, University Hospital of Tampere and University of Tampere, Medical School, Tampere, Finland.
8 Fay J. Lindner Center for Autism and Developmental Disorders, North Shore-Long Island Jewish Health System, 4300 Hempstead Turnpike, Bethpage, NY 11714, USA.
9 Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232-8548, USA.
10 Departments of Genetics and Development, and Pediatrics, Columbia University, New York, NY 10027, USA.
11 Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WCIN 1EH, UK.
12 Interdepartmental Program in the Neurosciences, Program in Neurogenetics, Neurology Department, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1769, USA.
13 Department of Human Genetics, The University of Chicago, 920 East 58th Street, Chicago, IL 60637, USA.
14 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
* To whom correspondence should be addressed.
Jonathan Sebat , E-mail: sebat@cshl.edu
Michael Wigler , E-mail: wigler@cshl.edu
We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (2%) of patients with an affected first-degree relative, and in 2 out of 196 (1.0%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
