Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness
Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness
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DOI：
10.1038/mp.2016.24
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发表时间：
2016-12-01
影响因子：
11
通讯作者：
DeLisi, L. E.
中科院分区：
文献类型：
--
作者：
Homann, O. R.;Misura, K.;DeLisi, L. E.
精神遗传学目前的焦点是通过非常大的全基因组关联研究分析来检测多个常见风险等位基因。然而，确实存在这样的家庭，尽管很少见，有多个受影响的成员，他们被认为对他们的疾病有类似的遗传原因。我们推测，在这些家庭中的一些可能有罕见的高度渗透突变，与疾病隔离。在这项探索性研究中，对9个家族的90个个体的基因组进行了测序。每个家庭包括至少三个受精神病影响的亲属和三个未受影响的亲属。26种变异被鉴定为家族私有，改变蛋白质序列，并传播给家族内所有测序的受影响个体。在一个家庭中，7个患有精神分裂症谱系障碍的兄弟姐妹每个人都在SHANK2基因中携带一种新的私人错义变体。该变体位于SH3蛋白结合基序内，SHANK2可通过该基序与突触后谷氨酸受体相互作用。在另一个家庭中，四个受影响的兄弟姐妹和他们未受影响的母亲每个人都在X染色体上的SMARCA1基因中携带一种新的私人错义变体。这两种变体代表的候选人，可能是因果关系的精神障碍时，考虑到其传播模式和已知的基因和疾病的生物学。
A current focus in psychiatric genetics is detection of multiple common risk alleles through very large genome-wide association study analyses. Yet families do exist, albeit rare, that have multiple affected members who are presumed to have a similar inherited cause to their illnesses. We hypothesized that within some of these families there may be rare highly penetrant mutations that segregate with illness. In this exploratory study, the genomes of 90 individuals across nine families were sequenced. Each family included a minimum of three available relatives affected with a psychotic illness and three available unaffected relatives. Twenty-six variants were identified that are private to a family, alter protein sequence, and are transmitted to all sequenced affected individuals within the family. In one family, seven siblings with schizophrenia spectrum disorders each carry a novel private missense variant within the SHANK2 gene. This variant lies within the consensus SH3 protein-binding motif by which SHANK2 may interact with post-synaptic glutamate receptors. In another family, four affected siblings and their unaffected mother each carry a novel private missense variant in the SMARCA1 gene on the X chromosome. Both variants represent candidates that may be causal for psychotic disorders when considered in the context of their transmission pattern and known gene and disease biology.