生物谷報道：最新研究結(jié)果顯示，最少一半的男性自閉癥（autism）病例是由自發(fā)遺傳突變引起的,。遺傳有這些突變的個體，其子女罹患自閉癥的風險很高,。詳細內(nèi)容刊登于PNAS,。
自閉癥患者有社交障礙，興趣范圍狹窄,。每1000人中就有3－6名有自閉癥傾向,，但病因不明，專家推測其可能與遺傳有關(guān),。紐約Albert Einstein醫(yī)學院神經(jīng)學家Isabelle Rapin說：“遺傳在自閉癥中發(fā)揮主要作用,，這是20多年來的共識……遺傳學證據(jù)也并不矛盾。”但弄清基因影響自閉癥的確切機制卻并非易事,。自閉癥是一種復(fù)雜疾病,，癥狀范圍廣泛且很嚴重。由于某種未知原因,，男性患者是女性患者的四倍,。
自發(fā)突變
今年早期進行一次基因組范圍內(nèi)掃描，將某些自閉癥病例與某些基因的拷貝數(shù)突變聯(lián)系起來,。10％的自閉癥患者有其余患者中不存在的拷貝數(shù)突變,，說明突變是自發(fā)的。但文章第一作者,、冷泉港實驗室遺傳學家Michael Wigler強調(diào),，可能此研究錯失了一些拷貝數(shù)突變。“我們可以肯定,，10％這個數(shù)字是低估了,。”因此，Wigler與其同事轉(zhuǎn)向一個記錄家庭中有兩個或者兩個以上自閉癥兒童的家譜數(shù)據(jù)庫,，試圖弄清頭兩個孩子患有自閉癥的家庭,，第三個孩子患有自閉癥的幾率有多大。所調(diào)查的86個家庭中,，頭兩個孩子是自閉癥患者,，第三個孩子是男性,，結(jié)果其中42個排行第三的孩子有自閉癥癥狀。這說明患者將突變傳給后代的幾率為1/2,。另一個數(shù)據(jù)庫研究得到了相似的結(jié)論,。
利用數(shù)學模型，Wigler小組發(fā)現(xiàn)描述這種自閉癥遺傳的最為簡單的方法是將患者分為兩個風險級別,，攜帶一個之前存在的自閉癥誘發(fā)突變的人群和不攜帶此突變的人群,。該模型強調(diào)，大約一半的自閉癥兒童來的父母,，之前沒有明顯的自閉癥遺傳學特征,，說明這些兒童的自閉癥是由自發(fā)突變引起的。傾向于有自閉癥子女的高齡母親,，也可歸為此列,。高齡母親的卵子有更多的機會積累突變。
這些自發(fā)突變一旦傳遞下去,，其后代——特別是女性后代,，毫無癥狀地攜帶突變——更有可能得到自閉癥子女。攜帶此突變的男性,，也應(yīng)該有遺傳給后代的可能,，但也許因為自閉癥而不會有后代。最新研究模式提示,，約1/4的自閉癥兒童從其父母處獲得一個拷貝數(shù)突變,。
“這是觀察數(shù)據(jù)的一種新方式，”Papin說,，但該模型還需要經(jīng)過更多數(shù)據(jù)的檢驗,。自閉癥也可能與其它因素如妊娠期并發(fā)癥以及多重基因的影響有關(guān)。
原始出處:
Published online before print July 25, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0705803104
OPEN ACCESS ARTICLE
Genetics
A unified genetic theory for sporadic and inherited autism
( human genetics | neurodevelopmental disorders | population genetics )
Xiaoyue Zhao *, Anthony Leotta *, Vlad Kustanovich , Clara Lajonchere , Daniel H. Geschwind , Kiely Law , Paul Law , Shanping Qiu ¶, Catherine Lord ¶, Jonathan Sebat *, Kenny Ye ||**, and Michael Wigler ***
*Cold Spring Harbor Laboratory, 1 Bungtown Road, P.O. Box 100, Cold Spring Harbor, NY 11724; Autism Genetic Resource Exchange, Cure Autism Now, 5455 Wilshire Boulevard, Suite 2250, Los Angeles, CA 90036; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1769; Department of Medical Informatics, and Interactive Autism Network, Kennedy Krieger Institute, Baltimore, MD 21205; ¶University of Michigan Autism and Communication Disorders Center, 1111 East Catherine Street, Ann Arbor, MI 48109-2054; and ||Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461
Contributed by Michael Wigler, June 20, 2007 (sent for review June 1, 2007)
Autism is among the most clearly genetically determined of all cognitive-developmental disorders, with males affected more often than females. We have analyzed autism risk in multiplex families from the Autism Genetic Resource Exchange (AGRE) and find strong evidence for dominant transmission to male offspring. By incorporating generally accepted rates of autism and sibling recurrence, we find good fit for a simple genetic model in which most families fall into two types: a small minority for whom the risk of autism in male offspring is near 50%, and the vast majority for whom male offspring have a low risk. We propose an explanation that links these two types of families: sporadic autism in the low-risk families is mainly caused by spontaneous mutation with high penetrance in males and relatively poor penetrance in females; and high-risk families are from those offspring, most often females, who carry a new causative mutation but are unaffected and in turn transmit the mutation in dominant fashion to their offspring.
