Pantoja-Melendez Carlos, Ali Manir, Zenteno Juan C
Research Unit-Genetics, Institute of Ophthalmology, "Conde de Valenciana," Mexico City, Mexico ; Department of Public Health, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.
Mol Vis. 2013 Aug 27;19:1866-70. eCollection 2013.
To investigate the molecular epidemiological basis for the unusually high incidence of sclerocornea, aphakia, and microphthalmia in a village in the Tlaxcala province of central Mexico.
A population census was performed in a village to identify all sclerocornea, aphakia, and microphthalmia cases. Molecular analysis of the previously identified Forkhead box protein E3 (FOXE3) mutation, c.292T>C (p.Y98H), was performed with PCR amplification and direct DNA sequencing. In addition, DNA from 405 randomly selected unaffected villagers was analyzed to establish the carrier frequency of the causal mutation. To identify the number of generations since the mutation arose in the village, 17 polymorphic markers distributed in a region of 6 Mb around the mutated locus were genotyped in the affected individuals, followed by DMLE software analysis to calculate mutation age.
A total of 22 patients with sclerocornea, aphakia, and microphthalmia were identified in the village, rendering a disease prevalence of 2.52 cases per 1,000 habitants (1 in 397). The FOXE3 homozygous mutation was identified in all 17 affected subjects who consented to molecular analysis. Haplotype analysis indicated that the mutation arose 5.0-6.5 generations ago (approximately 106-138 years). Among the 405 unaffected villagers who were genotyped, ten heterozygote carriers were identified, yielding a population carrier frequency of approximately 1 in 40 and a predicted incidence of affected of 1 in 6,400 based on random marriages between two carriers in the village.
This study demonstrates that a cluster of patients with sclerocornea, aphakia, and microphthalmia in a small Mexican village is due to a FOXE3 p.Y98H founder mutation that arose in the village just over a century ago at a time when a population migrated from a nearby village because of land disputes. The actual disease incidence is higher than the calculated predicted value and suggests non-random marriages (i.e., consanguinity) within the population. We can now offer the community more informed genetic counseling based on an accurate genetic test, thus increasing the likelihood of a better outcome for the families.
调查墨西哥中部特拉斯卡拉州一个村庄中巩膜角膜、无晶状体和小眼症异常高发的分子流行病学基础。
在一个村庄进行人口普查，以确定所有巩膜角膜、无晶状体和小眼症病例。采用聚合酶链反应（PCR）扩增和直接DNA测序对先前鉴定出的叉头框蛋白E3（FOXE3）突变c.292T>C（p.Y98H）进行分子分析。此外，对405名随机选择的未受影响村民的DNA进行分析，以确定致病突变的携带者频率。为了确定该突变在村庄中出现后的世代数，对受影响个体中分布在突变位点周围6兆碱基区域内的17个多态性标记进行基因分型，随后通过DMLE软件分析计算突变年龄。
在该村庄共鉴定出22例巩膜角膜、无晶状体和小眼症患者，疾病患病率为每1000名居民中有2.52例（1/397）。在所有17名同意进行分子分析的受影响受试者中均鉴定出FOXE3纯合突变。单倍型分析表明，该突变发生在5.0 - 6.5代之前（约106 - 138年）。在进行基因分型的405名未受影响村民中，鉴定出10名杂合子携带者，人群携带者频率约为1/40，基于村庄中两名携带者之间的随机婚配，预测患病几率为1/6400。
本研究表明，墨西哥一个小村庄中一群巩膜角膜、无晶状体和小眼症患者是由于一个FOXE3 p.Y98H始祖突变所致，该突变于一个多世纪前在村庄出现，当时由于土地纠纷，一群人从附近村庄迁移至此。实际疾病发病率高于计算出的预测值，提示人群中存在非随机婚配（即近亲结婚）。我们现在可以基于准确的基因检测为社区提供更明智的遗传咨询，从而增加家庭获得更好结果的可能性。
