Genometrics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institute of Health (NIH), Baltimore, MD 21224, USA.
Statistical Genetics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institute of Health (NIH), Baltimore, MD 21224, USA.
Genes (Basel). 2022 May 3;13(5):816. doi: 10.3390/genes13050816.
Craniosynostosis (CS) is a major birth defect in which one or more skull sutures fuse prematurely. We previously performed a genome-wide association study (GWAS) for sagittal non-syndromic CS (sNCS), identifying associations downstream from on 20p12.3 and intronic to on 7p14.3; analyses of imputed variants in on 3q29 were also genome-wide significant. We followed this work with a GWAS for metopic non-syndromic NCS (mNCS), discovering a significant association intronic to on 20q13.31. In the current study, we sequenced the associated regions on 3q29, 7p14.3, and 20p12.3, including two candidate genes ( and near some of these regions in 83 sNCS child-parent trios, and sequenced regions on 7p14.3 and 20q13.2-q13.32 in 80 mNCS child-parent trios. These child-parent trios were selected from the original GWAS cohorts if the probands carried at least one copy of the top associated GWAS variant (rs1884302 C allele for sNCS; rs6127972 T allele for mNCS). Many of the variants sequenced in these targeted regions are strongly predicted to be within binding sites for transcription factors involved in craniofacial development or bone morphogenesis. Variants enriched in more than one trio and predicted to be damaging to gene function are prioritized for functional studies.
颅缝早闭（CS）是一种主要的出生缺陷，其中一个或多个颅骨缝过早融合。我们之前对矢状非综合征性 CS（sNCS）进行了全基因组关联研究（GWAS），确定了 20p12.3 下游和 7p14.3 内含子处与 之间的关联；3q29 处的推断变异分析也具有全基因组意义。在此基础上，我们对额状非综合征性 NCS（mNCS）进行了 GWAS，发现 20q13.31 内含子处存在显著关联。在当前研究中，我们对 3q29、7p14.3 和 20p12.3 上的相关区域进行了测序，包括两个候选基因（和 ），这些基因位于其中一些区域附近，在 83 个 sNCS 亲子三对中，我们对 7p14.3 和 20q13.2-q13.32 区域进行了测序。这些亲子三对是从原始 GWAS 队列中选择的，如果先证者携带至少一个顶级关联 GWAS 变体的副本（sNCS 的 rs1884302 C 等位基因；mNCS 的 rs6127972 T 等位基因）。在这些靶向区域中测序的许多变体强烈预测为参与颅面发育或骨形态发生的转录因子的结合位点。在多个三对中富集且预测对基因功能有害的变体被优先用于功能研究。
