Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory
Mutations in the CHD7 Gene: The Experience of a Commercial Laboratory
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DOI：
10.1089/gtmb.2010.0101
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发表时间：
2010-12-01
影响因子：
1.4
通讯作者：
Bale, Sherri
中科院分区：
文献类型：
--
作者：
Bartels, Cynthia F.;Scacheri, Cheryl;Bale, Sherri
CHARGE 综合征是一种常染色体显性多系统疾病，由编码染色结构域解旋酶 DNA 结合蛋白 7 的 CHD7 基因突变引起。自 2005 年以来，CHD7 突变的分子诊断测试已在临床环境中可用。我们在此报告了首批提交测试的 642 个无关先证者样本的结果。百分之三十二 (n = 203) 的患者样本鉴定出杂合致病变异。突变率低于已发表的充分表征的临床样本的突变率可能是由于转介偏倚，因为提交用于临床测试的样本可能是为了“排除”诊断，而不仅仅是为了确认临床怀疑。我们鉴定了 159 个独特的致病性突变，其中，每个个体都有 134 个突变，在两到五个个体 (n = 69) 中发现了 25 个突变。在 203 个突变中，只有 9 个是错义的，其中 107 个是错义的。无意义、69 个移码和 15 个剪接位点突变可能导致细胞水平上的单倍体不足。在 642 个测试样本中发现的另外 72 个变异 (11%) 被认为具有未知的临床意义。旨在作为临床医生、遗传咨询师、研究人员和其他诊断实验室的资源。
CHARGE syndrome is an autosomal dominant multisystem disorder caused by mutation in the CHD7 gene, encoding chromodomain helicase DNA-binding protein 7. Molecular diagnostic testing for CHD7 mutation has been available in a clinical setting since 2005. We report here the results from the first 642 unrelated proband samples submitted for testing. Thirty-two percent (n = 203) of patient samples had a heterozygous pathogenic variant identified. The lower mutation rate than that published for well-characterized clinical samples is likely due to referral bias, as samples submitted for clinical testing may be for "rule-out'' diagnoses, rather than solely to confirm clinical suspicion. We identified 159 unique pathogenic mutations, and of these, 134 mutations were each seen in a single individual and 25 mutations were found in two to five individuals (n = 69). Of the 203 mutations, only 9 were missense, with 107 nonsense, 69 frameshift, and 15 splice-site mutations likely leading to haploinsufficiency at the cellular level. An additional 72 variations identified in the 642 tested samples (11%) were considered to have unknown clinical significance. Copy number changes (deletion/duplication of the entire gene or one/several exons) were found to account for a very small number of cases (n = 3). This cohort represents the largest CHARGE syndrome sample size to date and is intended to serve as a resource for clinicians, genetic counselors, researchers, and other diagnostic laboratories.