A Higher Mutational Burden in Females Supports a "Female Protective Model" in Neurodevelopmental Disorders
A Higher Mutational Burden in Females Supports a "Female Protective Model" in Neurodevelopmental Disorders
复制标题
DOI：
10.1016/j.ajhg.2014.02.001
复制
发表时间：
2014-03-06
影响因子：
9.8
通讯作者：
Eichler, Evan E.
中科院分区：
文献类型：
--
作者：
Jacquemont, Sebastien;Coe, Bradley P.;Eichler, Evan E.
在一些神经发育障碍（NDs）中，男性患病率不断增加，这导致了“女性保护模式”的概念。我们研究了这种基于性别的倾向性差异的分子基础，并证明在15585个确定为NDs的先证队列中，与男性相比，女性中有害的常染色体拷贝数变异（CNVs）过多（优势比[OR] = 1.46, p = 8 × 10(-10)）。在一个由762个家庭组成的独立自闭症谱系障碍（ASD）队列中，我们发现女性的有害常染色体cnv增加了3倍（p = 7 × 10(-4)），并且与男性先证相比，女性的有害单核苷酸变异（snv）过量（OR = 1.34, p = 0.03）。我们还发现，常染色体snv的危害性在女性先证者中显著更高（p = 0.0006）。在NDs先证者的父母中也观察到类似的偏倚。有害CNVs （bb0 400kb）比小CNVs < 400kb （OR = 1.45, p = 0.0003）更常被母系遗传（高达64%，p = 10(-15)）。在ASD队列中，有害的CNVs和SNVs也观察到母体传播增加。尽管ASD女性表现出较高的突变负担和较低的认知能力，但即使在对这些认知差异进行调整后，过量的突变负担仍然存在。这些结果强烈表明，女性的病因负担增加与X染色体上罕见的有害变异无关。需要仔细的表型和基因分型队列来确定症状，这些症状显示出对突变负担的性别特异性倾向性。
Increased male prevalence has been repeatedly reported in several neurodevelopmental disorders (NDs), leading to the concept of a "female protective model." We investigated the molecular basis of this sex-based difference in liability and demonstrated an excess of deleterious autosomal copy-number variants (CNVs) in females compared to males (odds ratio [OR] = 1.46, p = 8 x 10(-10)) in a cohort of 15,585 probands ascertained for NDs. In an independent autism spectrum disorder (ASD) cohort of 762 families, we found a 3-fold increase in deleterious autosomal CNVs (p = 7 x 10(-4)) and an excess of private deleterious single-nucleotide variants (SNVs) in female compared to male probands (OR = 1.34, p = 0.03). We also showed that the deleteriousness of autosomal SNVs was significantly higher in female probands (p = 0.0006). A similar bias was observed in parents of probands ascertained for NDs. Deleterious CNVs (>400 kb) were maternally inherited more often (up to 64%, p = 10(-15)) than small CNVs < 400 kb (OR = 1.45, p = 0.0003). In the ASD cohort, increased maternal transmission was also observed for deleterious CNVs and SNVs. Although ASD females showed higher mutational burden and lower cognition, the excess mutational burden remained, even after adjustment for those cognitive differences. These results strongly suggest that females have an increased etiological burden unlinked to rare deleterious variants on the X chromosome. Carefully phenotyped and genotyped cohorts will be required for identifying the symptoms, which show gender-specific liability to mutational burden.