A homozygous deletion of a normal variation locus in a patient with hearing loss from non-consanguineous parents
A homozygous deletion of a normal variation locus in a patient with hearing loss from non-consanguineous parents
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DOI：
10.1136/jmg.2008.063685
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发表时间：
2009-06-01
影响因子：
4
通讯作者：
Szuhai, K.
中科院分区：
文献类型：
--
作者：
Knijnenburg, J.;Oberstein, S. A. J. Lesnik;Szuhai, K.
背景：包含人类基因组拷贝数变异信息的国际数据库是使用高分辨率全基因组筛选的实验室的重要参考。在寻找患者的致病性拷贝数变化时，可以使用这些数据库过滤掉在健康人群中检测到的基因组缺失或重复，从而标记为正常拷贝数变异（CNV）。然而，这种策略的一个潜在缺陷是，报告的正常 CNV 通常不会引起进一步的研究，因此当它们以（致病性）纯合状态存在时可能仍然未被识别。因此，纯合状态下的 CNV 对疾病的影响可能仍未被发现和低估。 方法和结果：在患有综合征性听力损失的患者中，阵列比较基因组杂交（阵列 CGH）和多重连接依赖性探针扩增（MLPA）揭示了 CNV 15q15.3 上的纯合缺失，遗传自半合子携带者父母。该缺失约为 90 KB，包含四个基因，其中包括 STRC 基因，该基因与常染色体隐性耳聋 (DFNB16) 有关。通过筛选健康对照个体并审查公开的 CNV 数据，我们估计半合子缺失携带者的频率约为 1.6%。 结论：我们通过一组分子工具描述了导致综合征性听力损失的 CNV 区域纯合性缺失。与半合子缺失的估计频率一起，这些结果强调了 15q15.3 基因座在（综合症）听力障碍患者中的作用。此外，此案例说明了不自动从进一步分析中消除已注册 CNV 的重要性。
Background: International databases with information on copy number variation of the human genome are an important reference for laboratories using high resolution whole genome screening. Genomic deletions or duplications which have been detected in the healthy population and thus marked as normal copy number variants (CNVs) can be filtered out using these databases when searching for pathogenic copy number changes in patients. However, a potential pitfall of this strategy is that reported normal CNVs often do not elicit further investigation, and thus may remain unrecognised when they are present in a (pathogenic) homozygous state. The impact on disease of CNVs in the homozygous state may thus remain undetected and underestimated.Methods and results: In a patient with syndromic hearing loss, array comparative genomic hybridisation (array CGH) and multiple ligation dependent probe amplification (MLPA) revealed a homozygous deletion on 15q15.3 of a CNV, inherited from hemizygous carrier parents. The deletion is about 90 kilobases and contains four genes including the STRC gene, which is involved in autosomal recessive deafness (DFNB16). By screening healthy control individuals and review of publicly available CNV data we estimated the frequency of hemizygous deletion carriers to be about 1.6%.Conclusion: We characterised a homozygous deletion of a CNV region causing syndromic hearing loss by a panel of molecular tools. Together with the estimated frequency of the hemizygous deletion, these results emphasise the role of the 15q15.3 locus in patients with (syndromic) hearing impairment. Furthermore, this case illustrates the importance of not automatically eliminating registered CNVs from further analysis.