Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
PLoS One. 2012;7(7):e41902. doi: 10.1371/journal.pone.0041902. Epub 2012 Jul 27.
Retinitis pigmentosa and other hereditary retinal degenerations (HRD) are rare genetic diseases leading to progressive blindness. Recessive HRD are caused by mutations in more than 100 different genes. Laws of population genetics predict that, on a purely theoretical ground, such a high number of genes should translate into an extremely elevated frequency of unaffected carriers of mutations. In this study we estimate the proportion of these individuals within the general population, via the analyses of data from whole-genome sequencing.
METHODOLOGY/PRINCIPAL FINDINGS: We screened complete and high-quality genome sequences from 46 control individuals from various world populations for HRD mutations, using bioinformatic tools developed in-house. All mutations detected in silico were validated by Sanger sequencing. We identified clear-cut, null recessive HRD mutations in 10 out of the 46 unaffected individuals analyzed (∼22%).
CONCLUSIONS/SIGNIFICANCE: Based on our data, approximately one in 4-5 individuals from the general population may be a carrier of null mutations that are responsible for HRD. This would be the highest mutation carrier frequency so far measured for a class of Mendelian disorders, especially considering that missenses and other forms of pathogenic changes were not included in our assessment. Among other things, our results indicate that the risk for a consanguineous couple of generating a child with a blinding disease is particularly high, compared to other genetic conditions.
色素性视网膜炎和其他遗传性视网膜变性（HRD）是导致进行性失明的罕见遗传病。隐性 HRD 是由 100 多个不同基因的突变引起的。群体遗传学定律预测，仅从理论上讲，如此多的基因应该导致突变的未受影响携带者的极高频率。在这项研究中，我们通过对来自不同世界人群的 46 名对照个体的全基因组测序数据进行分析，来估计这些个体在普通人群中的比例。
方法/主要发现：我们使用内部开发的生物信息学工具，对来自各种世界人群的 46 名对照个体的完整和高质量基因组序列进行了 HRD 突变筛查。通过计算机检测到的所有突变均通过 Sanger 测序进行了验证。在分析的 46 名未受影响个体中，我们确定了 10 名个体存在明确的隐性 HRD 突变（约 22%）。
结论/意义：根据我们的数据，普通人群中约每 4-5 人就可能是导致 HRD 的隐性突变携带者。这将是迄今为止针对孟德尔疾病类别的最高突变携带者频率，尤其是考虑到我们的评估中未包括错义突变和其他形式的致病性变化。除其他外，我们的结果表明，与其他遗传条件相比，近亲夫妇生育患有致盲疾病的孩子的风险特别高。
