Association of a rare NOTCH4 coding variant with systemic sclerosis: a family-based whole exome sequencing study
Association of a rare NOTCH4 coding variant with systemic sclerosis: a family-based whole exome sequencing study
复制标题
DOI：
10.1186/s12891-016-1320-4
复制
发表时间：
2016-11-09
影响因子：
2.3
通讯作者：
Hakonarson, Hakon
中科院分区：
文献类型：
--
作者：
Cardinale, Christopher J.;Li, Dong;Hakonarson, Hakon
背景：系统性硬化症（SSc）是一种多因素病因的风湿病。全基因组关联研究暗示了一种多基因、复杂的遗传模式，其中包括人类白细胞抗原位点的变异和6p21染色体上一个位点的非编码变异，以及其他影响不大的位点。在这里，我们描述了一个8岁的女性先证者，表现为弥漫性皮肤SSc/硬皮病，并有祖父和姨妈的SSc家族史。方法：对该家族3名成员进行全外显子组测序（WES）。我们检查了罕见的错义、无义、剪接改变和与常染色体显性遗传模型相匹配的编码索引。我们选择了一个错义变异进行Sanger测序确认，基于其对已知SSc基因座基因功能和位置的预测影响。结果：生物信息学分析发现8个候选变异符合我们的标准。我们在NOTCH4的调控NODP域中发现了一个非常罕见的错义变体，位于6p21位点，c. 4245G > a: p. Met1415Ile，与表型分离。根据外显子组聚集联盟的数据，该等位基因的频率为1.83 × 10（-5）。结论：该家族提示了一种新的SSc发病机制，其中一种罕见的、渗透的编码变异可以显著提高疾病风险，而在该位点通常发现的非编码变异则更为温和。这些结果表明，NOTCH4基因的调节可能是SSc染色体6p21上的关联信号的原因。
Background: Systemic sclerosis (SSc) is a rheumatologic disease with a multifactorial etiology. Genome-wide association studies imply a polygenic, complex mode of inheritance with contributions from variation at the human leukocyte antigen locus and non-coding variation at a locus on chromosome 6p21, among other modestly impactful loci. Here we describe an 8-year-old female proband presenting with diffuse cutaneous SSc/ scleroderma and a family history of SSc in a grandfather and maternal aunt.Methods: We employed whole exome sequencing (WES) of three members of this family. We examined rare missense, nonsense, splice-altering, and coding indels matching an autosomal dominant inheritance model. We selected one missense variant for Sanger sequencing confirmation based on its predicted impact on gene function and location in a known SSc genetic locus.Results: Bioinformatic analysis found eight candidate variants meeting our criteria. We identified a very rare missense variant in the regulatory NODP domain of NOTCH4 located at the 6p21 locus, c. 4245G > A: p. Met1415Ile, segregating with the phenotype. This allele has a frequency of 1.83 x 10(-5) by the data of the Exome Aggregation Consortium.Conclusion: This family suggests a novel mechanism of SSc pathogenesis in which a rare and penetrant coding variation can substantially elevate disease risk in contrast to the more modest non-coding variation typically found at this locus. These results suggest that modulation of the NOTCH4 gene might be responsible for the association signal at chromosome 6p21 in SSc.