Effect of inbreeding on intellectual disability revisited by trio sequencing
Effect of inbreeding on intellectual disability revisited by trio sequencing
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DOI：
10.1111/cge.13463
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发表时间：
2019-01-01
影响因子：
3.5
通讯作者：
Ropers, Hans-Hilger
中科院分区：
文献类型：
--
作者：
Kahrizi, Kimia;Hu, Hao;Ropers, Hans-Hilger
在远交的西方人群中，大多数患有智力残疾（ID）的个体是散发性病例，显性从头突变（DNM）很常见，常染色体隐性ID（ARID）非常罕见。由于父母的近亲比例很高，这增加了患ARID和其他隐性疾病的风险，因此ID的患病率在近东和中东国家明显更高。事实上，在近亲家庭中的纯合性作图和测序已经确定了大量的ARID基因，但由于这些研究的设计，DNM不能系统地评估，并且通过避免近亲婚姻或通过携带者检测可能预防的病例的比例迄今未知。这促使我们对来自伊朗的100名散发性ID患者及其健康的近亲父母进行全外显子组测序。在61例患者中，我们确定了已知ID基因的明显致病变化。其中，44个是纯合隐性和17个显性DNMs。假设DNM率是稳定的，这些结果表明，父母的血缘关系增加了ID的风险约3.6倍，约4.1至4.25倍的第一堂兄弟姐妹工会的孩子。这些结果与最近的观点并不一致，最近的观点认为与血缘相关的健康风险通常很小，并且在过去被“夸大”了。
In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near- and middle-east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole-exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6-fold, and about 4.1 to 4.25-fold for children of first-cousin unions. These results do not rhyme with recent opinions that consanguinity-related health risks are generally small and have been "overstated" in the past.