Identification and analysis of the genetic causes in nine unrelated probands with syndromic craniosynostosis
Identification and analysis of the genetic causes in nine unrelated probands with syndromic craniosynostosis
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9例无亲属关系的综合征性颅缝早闭先证者的遗传原因鉴定及分析
DOI：
10.1016/j.gene.2017.10.041
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发表时间：
2018-01-30
期刊：
影响因子：
3.5
通讯作者：
Bao, Nan
中科院分区：
文献类型：
--
作者：
Xu, Yufei;Sun, Shouqing;Bao, Nan
综合征性颅缝早闭是一组具有高度异质性的多种疾病，许多罕见的综合征仍有待鉴定。为确定和分析9例以综合征型颅缝早闭为主要表现的无亲缘关系先证者的致病性遗传变异，我们查阅了患者的相关医学资料，并进行了全外显子测序，进一步用桑格测序和父母背景进行验证。采用生物信息学分析方法，通过进化保守性比对、多线计算机预测和群体数据集（对照组和患者组）中等位基因频率，评估每个遗传变异的潜在有害或有益影响。采用美国医学遗传学和基因组学学会的标准和指南对每种遗传变异的致病性进行分类和解释。9例先证者均携带可能致病的突变体，其中3例突变体包括2个错义突变（IFFT 122基因c.3385C > T，SMC 1A基因c.3581A > G）和1个移码突变（TWISTI基因c.434dupA），均未见文献报道。我们认为由SMC 1A变异引起的科尔内利亚德兰格综合征是一种被忽视的综合征性颅缝早闭。我们的研究不仅扩大了罕见综合征的基因型和表型谱，而且证实了存在潜在的遗传机制。我们强调，仔细选择潜在的候选人和全面的检测方法进行遗传分析是重要的，以提高综合征型颅缝早闭症的遗传诊断率。
Syndromic craniosynostosis is a group of multiple conditions with high heterogeneity, and many rare syndromes still remain to be characterized. To identify and analyze causative genetic variants in nine unrelated probands mainly manifested as syndromic craniosynostosis, we reviewed the relevant medical information of the patients and performed the whole exome sequencing, further verified with Sanger sequencing and parental background. Bioinformatics analysis was used to evaluate the potential deleterious or benign effect of each genetic variant through evolutionary conservation alignment, multi-lines of computer predication and the allele frequency in population dataset (control and patient). The Standards and guidelines from American College of Medical Genetics and Genomics was used to classify and interpret the pathogenicity for each genetic variant. All the nine probands were found to carry the possibly causative variants, among which three variants including two missense mutations (c.3385C > T in IFT122 gene, c.3581A > G in SMC1A gene) and a frameshift mutation (c.434dupA in TWISTI gene) have never been reported in patients before. We suggested Cornelia de Lange syndrome caused by SMC1A variant is a neglected syndromic craniosynostosis. Our study not only expanded genotypic and phenotypic spectrum of the rare syndromes, but also confirmed that there existed an underlying genetic mechanism. We emphasized that deliberate selection of both the potential candidates and comprehensive detection methods for genetic analysis is important to increase the genetic diagnosis yield of syndromic craninosynostosis.