Discovery of variants unmasked by hemizygous deletions
Discovery of variants unmasked by hemizygous deletions
复制标题
DOI：
10.1038/ejhg.2011.263
复制
发表时间：
2012-07-01
影响因子：
5.2
通讯作者：
Cuppen, Edwin
中科院分区：
文献类型：
--
作者：
Hochstenbach, Ron;Poot, Martin;Cuppen, Edwin
基于阵列的全基因组节段非整倍性筛查可检测从头变异和遗传性拷贝数变异 (CNV)。在散发患者中，新生 CNV 被解释为潜在致病性。然而，从健康父母遗传的缺失，如果与从另一个健康父母遗传的突变的第二等位基因重叠，则可能具有致病性。为了检测此类事件，我们对 20 名患者的独特半合子缺失区域内的所有基因的整个编码序列（1.53 Mb 捕获足迹）进行了多重富集和新一代测序。在检测到的 703 个非同义单核苷酸变异 (SNV) 中，有 8 个代表因半合子缺失而暴露的变异。尽管遗传模式、格兰瑟姆矩阵评分、进化保守性和生物信息学预测的评估并不能一致地表明这些变异的致病性，但如果没有功能验证，就无法得出明确的结论。然而，在一名患有严重精神发育迟滞、言语缺失、小头畸形、唇颌腭裂和双侧听力损失的患者中，我们发现了第二个较小的缺失，该缺失遗传自另一位健康父母，导致高度保守的热休克因子结合蛋白1（HSBP1）基因的两个等位基因丢失。可以想象，遗传性缺失可能会揭示罕见的致病变异，这些变异可能通过隐性的基因作用模式产生表型影响。欧洲人类遗传学杂志 (2012) 20, 748-753; doi：10.1038/ejhg.2011.263； 2012 年 1 月 18 日在线发布
Array-based genome-wide segmental aneuploidy screening detects both de novo and inherited copy number variations (CNVs). In sporadic patients de novo CNVs are interpreted as potentially pathogenic. However, a deletion, transmitted from a healthy parent, may be pathogenic if it overlaps with a mutated second allele inherited from the other healthy parent. To detect such events, we performed multiplex enrichment and next-generation sequencing of the entire coding sequence of all genes within unique hemizygous deletion regions in 20 patients (1.53 Mb capture footprint). Out of the detected 703 non-synonymous single-nucleotide variants (SNVs), 8 represented variants being unmasked by a hemizygous deletion. Although evaluation of inheritance patterns, Grantham matrix scores, evolutionary conservation and bioinformatic predictions did not consistently indicate pathogenicity of these variants, no definitive conclusions can be drawn without functional validation. However, in one patient with severe mental retardation, lack of speech, microcephaly, cheilognathopalatoschisis and bilateral hearing loss, we discovered a second smaller deletion, inherited from the other healthy parent, resulting in loss of both alleles of the highly conserved heat shock factor binding protein 1 (HSBP1) gene. Conceivably, inherited deletions may unmask rare pathogenic variants that may exert a phenotypic impact through a recessive mode of gene action. European Journal of Human Genetics (2012) 20, 748-753; doi: 10.1038/ejhg.2011.263; published online 18 January 2012