Gregory Michael D, Kolachana Bhaskar, Yao Yin, Nash Tiffany, Dickinson Dwight, Eisenberg Daniel P, Mervis Carolyn B, Berman Karen F
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive 3C-216, Bethesda, MD, 20892, USA.
Human Brain Collection Core, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
BMC Med Genet. 2018 Apr 4;19(1):53. doi: 10.1186/s12881-018-0563-3.
Williams syndrome ([WS], 7q11.23 hemideletion) and 7q11.23 duplication syndrome (Dup7) show contrasting syndromic symptoms. However, within each group there is considerable interindividual variability in the degree to which these phenotypes are expressed. Though software exists to identify areas of copy number variation (CNV) from commonly-available SNP-chip data, this software does not provide non-diploid genotypes in CNV regions. Here, we describe a method for identifying haploid and triploid genotypes in CNV regions, and then, as a proof-of-concept for applying this information to explain clinical variability, we test for genotype-phenotype associations.
Blood samples for 25 individuals with WS and 13 individuals with Dup7 were genotyped with Illumina-HumanOmni5M SNP-chips. PennCNV and in-house code were used to make genotype calls for each SNP in the 7q11.23 locus. We tested for association between the presence of aortic arteriopathy and genotypes of the remaining (haploid in WS) or duplicated (triploid in Dup7) alleles.
Haploid calls in the 7q11.23 region were made for 99.0% of SNPs in the WS group, and triploid calls for 98.8% of SNPs in those with Dup7. The G allele of SNP rs2528795 in the ELN gene was associated with aortic stenosis in WS participants (p < 0.0049) while the A allele of the same SNP was associated with aortic dilation in Dup7.
Commonly available SNP-chip information can be used to make haploid and triploid calls in individuals with CNVs and then to relate variability in specific genes to variability in syndromic phenotypes, as demonstrated here using aortic arteriopathy. This work sets the stage for similar genotype-phenotype analyses in CNVs where phenotypes may be more complex and/or where there is less information about genetic mechanisms.
威廉姆斯综合征（[WS]，7q11.23半侧缺失）和7q11.23重复综合征（Dup7）表现出相反的综合征症状。然而，在每组中，这些表型的表达程度存在相当大的个体间差异。虽然存在从常用的单核苷酸多态性芯片（SNP芯片）数据中识别拷贝数变异（CNV）区域的软件，但该软件在CNV区域中不提供非二倍体基因型。在此，我们描述了一种在CNV区域中识别单倍体和三倍体基因型的方法，然后，作为将该信息应用于解释临床变异性的概念验证，我们测试基因型与表型的关联。
对25名患有WS的个体和13名患有Dup7的个体的血液样本进行Illumina-HumanOmni5M SNP芯片基因分型。使用PennCNV和内部代码对7q11.23基因座中的每个SNP进行基因型判定。我们测试了主动脉病变的存在与其余（WS中的单倍体）或重复（Dup7中的三倍体）等位基因的基因型之间的关联。
在WS组中，99.0%的SNP在7q11.23区域被判定为单倍体，在患有Dup7的个体中，98.8%的SNP被判定为三倍体。ELN基因中SNP rs2528795的G等位基因与WS参与者的主动脉狭窄相关（p < 0.0049），而同一SNP的A等位基因与Dup7中的主动脉扩张相关。
常用的SNP芯片信息可用于对患有CNV的个体进行单倍体和三倍体判定，然后将特定基因的变异性与综合征表型的变异性相关联，如此处使用主动脉病变所证明的。这项工作为在CNV中进行类似的基因型-表型分析奠定了基础，在这些分析中，表型可能更复杂和/或关于遗传机制的信息较少。
