Intellectual Disability Is Associated with Increased Runs of Homozygosity in Simplex Autism
Intellectual Disability Is Associated with Increased Runs of Homozygosity in Simplex Autism
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DOI：
10.1016/j.ajhg.2013.06.004
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发表时间：
2013-07-11
影响因子：
9.8
通讯作者：
Morrow, Eric M.
中科院分区：
文献类型：
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作者：
Gamsiz, Ece D.;Viscidi, Emma W.;Morrow, Eric M.
智力残疾（ID），通常归因于常染色体隐性突变，发生在40%的自闭症谱系障碍（ASD）中。出于这个原因，我们进行了纯合性（ROH）在单纯ASD影响的家庭组成的先证者诊断为ASD和至少一个未受影响的兄弟姐妹的运行全基因组分析。在这些家庭中，智商70的先证者没有表现出这种过度。虽然ASD在男性中比女性更常见，但女性的比例随着智商的下降而增加。我们的数据确实支持ROH负担与女孩自闭症诊断之间的关联;然而，我们无法证明这种影响与低智商无关。我们还发现了几个自闭症候选基因，基于发现（1）在ROH间隔内并且在自闭症中复发的单个基因，或（2）在自闭症ROH块内并且在外显子组测序数据分析时含有纯合的罕见有害变体的基因。总之，我们的数据表明，自闭症和共同发生的智力残疾的参与者有一个独特的遗传结构，这种结构可能涉及到这个自闭症亚组的receptor遗传基因座的作用。
Intellectual disability (ID), often attributed to autosomal-recessive mutations, occurs in 40% of autism spectrum disorders (ASDs). For this reason, we conducted a genome-wide analysis of runs of homozygosity (ROH) in simplex ASD-affected families consisting of a proband diagnosed with ASD and at least one unaffected sibling. In these families, probands with an IQ 70 do not show this excess. Although ASD is far more common in males than in females, the proportion of females increases with decreasing IQ. Our data do support an association between ROH burden and autism diagnosis in girls; however, we are not able to show that this effect is independent of low IQ. We have also discovered several autism candidate genes on the basis of finding (1) a single gene that is within an ROH interval and that is recurrent in autism or (2) a gene that is within an autism ROH block and that harbors a homozygous, rare deleterious variant upon analysis of exome-sequencing data. In summary, our data suggest a distinct genetic architecture for participants with autism and co-occurring intellectual disability and that this architecture could involve a role for recessively inherited loci for this autism subgroup.