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

颅额鼻综合征（CFNS）是一种X-连锁疾病，表现为表型严重程度的矛盾性性逆转：女性特征性地具有额鼻发育不良、颅缝早闭和其他轻微畸形，但男性通常仅轻度受累于距离过远。尽管如此，男性出现在CFNS家系代表性不足，与受影响的女性相比，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，我们利用了最近发现的编码肝配蛋白-B1的EFNB 1基因的致病突变，调查了59个家族的分子改变（最近研究了20个，其他地方发表了20个）。我们确定了EFNB 1的第一个完全缺失，编目27个新的基因内突变，并使用焦磷酸测序和附近的多态性等位基因的分析，以量化马赛克的情况下，并确定验证的种系突变的父母的起源。体细胞嵌合体被证明在6个53信息的家庭，和17个生殖系突变的个人，其中父母的突变起源可以证明，15个来自父亲。我们的结论是，占相对稀缺的载体男性的主要因素是偏向突变的父系生殖系（目前作为受影响的女性后代）结合受影响的女性生殖健康降低。合子后突变也有助于女性的优势，而真正的nonbromatrance男性谁是半合子的EFNB 1突变似乎不寻常。这些结果强调了在CFNS家庭咨询中考虑可能的突变起源的重要性，并提供了一种普遍适用的方法来结合分析嵌合体和种系突变。

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.