De novo copy number variants associated with intellectual disability have a paternal origin and age bias
De novo copy number variants associated with intellectual disability have a paternal origin and age bias
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DOI：
10.1136/jmedgenet-2011-100147
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发表时间：
2011-11-01
影响因子：
4
通讯作者：
Veltman, Joris A.
中科院分区：
文献类型：
--
作者：
Hehir-Kwa, Jayne Y.;Rodriguez-Santiago, Benjamin;Veltman, Joris A.
研究背景新生突变和结构重排是智力残疾（ID）和其他生殖适应性降低或无效的疾病的常见原因。方法本研究利用单核苷酸多态性微阵列的信息，确定在3443例ID患者队列中检测到的118例罕见的从头拷贝数变异（CNVs）的起源父母。（76%，p=1.14x10（-8））起源于父系等位基因。这种父系偏倚与CNV长度和类型无关。有趣的是，对于两侧有节段性重复的CNVs，父系偏倚不太明显（64%），这表明罕见从头CNVs形成的分子机制可能依赖于起源的父母。此外，一个显着增加的父亲年龄只观察到那些CNVs两侧不段重复（p=0.02）。结论这表明，罕见的从头CNVs越来越多地产生与先进的父亲年龄在精子发生过程中的复制为基础的机制。
Background De novo mutations and structural rearrangements are a common cause of intellectual disability (ID) and other disorders with reduced or null reproductive fitness. Insight into the genomic and environmental factors predisposing to the generation of these de novo events is therefore of significant clinical importance.Methods This study used information from single nucleotide polymorphism microarrays to determine the parent-of-origin of 118 rare de novo copy number variations (CNVs) detected in a cohort of 3443 patients with ID.Results The large majority of these CNVs (76%, p=1.14x10(-8)) originated on the paternal allele. This paternal bias was independent of CNV length and CNV type. Interestingly, the paternal bias was less pronounced for CNVs flanked by segmental duplications (64%), suggesting that molecular mechanisms involved in the formation of rare de novo CNVs may be dependent on the parent-of-origin. In addition, a significantly increased paternal age was only observed for those CNVs which were not flanked by segmental duplications (p=0.02).Conclusion This indicates that rare de novo CNVs are increasingly being generated with advanced paternal age by replication based mechanisms during spermatogenesis.