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Analysis of polymorphism of the genes relating congenital anomalies : Basic approach for prevention of multifactorial disease

先天性异常相关基因多态性分析：预防多因素疾病的基本方法

基本信息

批准号：
18591966
负责人：
MATSUMOTO Kazuya
金额：
$ 2.32万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591966/
关键词：
craniofacial surgery gene mutation craniofrontonasal syndrome ephrin-B1

项目摘要

Craniofrontonasal syndrome (CFNS) is an X-linked disorder that exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis, and additional minor malformations, but males are usually mildly affected with hypertelorism only. Despite this, males appear underrepresented in CFNS pedigrees, with carrier males encountered infrequently compared with affected females. To investigate these unusual genetic features of CFNS, we exploited the recent discovery of causative mutations in the EFNB1 gene, which encodes ephrin-B1, to survey the molecular alterations in 59 families (se newly investigated and 20 published elsewhere). We identified the first complete deletions of EFNB1, catalogued 27 novel intragenic mutations, and used Pyrosequencing and analysis of nearby polymorphic alleles to quantify mosaic cases and to determine the parental origin of verified germline mutations. Somatic mosaicism was demonstrated in 6 of 53 informative families, and, of 17 germline mutations in individuals for whom the parental origin of mutation could be demonstrated, 15 arose from the father. We conclude that the major factor accounting for the relative scarcity of carrier males is the bias toward mutations in the paternal germline (which present as affected female offspring) combined with reduced reproductive fitness in affected females. Postzygotic mutations also contribute to the female preponderance, whereas true nonpenetrance in males who are hemizygous for an EFNB1 mutation appears unusual. These results highlight the importance of considering possible origins of mutation in the counseling of families with CFNS and provide a generally applicable approach to the combined analysis of mosaic and germline mutations.

颅咽管综合征(CFNS)是一种X连锁的疾病，在表型严重程度上表现出矛盾的性别反转：女性以额鼻发育不良、颅缝融合和额外的轻微畸形为特征，但男性通常只有轻微的端粒症。尽管如此，男性在CFNS家系中的代表性似乎很低，与患病的女性相比，携带者男性很少遇到。为了研究CFNS的这些不寻常的遗传特征，我们利用最近发现的EFNB1基因的致病突变，对59个家庭的分子变化进行了调查(这是新发现的研究和在其他地方发表的20个家庭)。我们鉴定了EFNB1的第一个完全缺失，编目了27个新的基因内突变，并使用焦磷酸测序和附近多态等位基因的分析来量化嵌合体病例，并确定已验证的种系突变的亲本来源。在53个有信息的家系中，有6个家系表现出体细胞嵌合体，在17个可以证明其父母突变来源的个体中，15个来自父亲。我们的结论是，男性携带者相对稀少的主要原因是偏向于父系生殖系的突变(表现为受影响的女性后代)，以及受影响女性的生殖适合度降低。合子后突变也有助于女性的优势，而EFNB1突变的半合子男性的真正不外显似乎不寻常。这些结果强调了在CFNS家庭咨询中考虑可能的突变来源的重要性，并为嵌合体和胚系突变的联合分析提供了一种普遍适用的方法。