Novel mutation identification and copy number variant detection via exome sequencing in congenital muscular dystrophy.
Novel mutation identification and copy number variant detection via exome sequencing in congenital muscular dystrophy.
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DOI：
10.1002/mgg3.1387
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发表时间：
2020-11
影响因子：
2
通讯作者：
Manzini MC
中科院分区：
文献类型：
--
作者：
Cauley ES;Pittman A;Mummidivarpu S;Karimiani EG;Martinez S;Moroni I;Boostani R;Podini D;Mora M;Jamshidi Y;Hoffman EP;Manzini MC
先天性肌营养不良症 1A 型 (MDC1A)，也称为 merosin 缺陷型先天性肌营养不良症 (CMD)，是由层粘连蛋白 α2 基因 (LAMA2) 突变引起的严重 CMD 形式。在莱顿开放变异数据库中发现的 300 多种可能的致病变异中，大多数是导致 LAMA2 功能完全丧失的截短突变，但也有不同频率的多拷贝数变异 (CNV) 报道。我们收集了一组被诊断出可能患有 MDC1A 的个体，并试图通过外显子组测序来识别单核苷酸变异以及小型和大型 CNV，通过扩展测序数据分析来检测剪接变化和 CNV。标准外显子组分析在我们的队列中发现了多个新的 LAMA2 变异，但只有 4 个病例携带双等位基因变异。由于可能的截短 LAMA2 变体通常在没有第二个等位基因的杂合性中发现，因此我们对外显子组数据进行了额外的剪接和 CNV 分析，并在其余 4 例中鉴定了规范序列之外的一个剪接变化和 3 个 CNV。我们的研究结果支持了这样的预期，即部分 MDC1A 病例可能是由至少一个 CNV 等位基因引起的，并表明如何通过对现有外显子组数据的额外分析来有效识别这些变化。外显子组测序分析可以识别先天性肌营养不良症病例中 LAMA2 中的新单核苷酸变异 (SNV) 和拷贝数变异 (CNV)。当仅发现一个 SNV 等位基因时，额外的 CNV 分析可以提供完整的基因诊断。
Congenital muscular dystrophy type 1A (MDC1A), also termed merosin‐deficient congenital muscular dystrophy (CMD), is a severe form of CMD caused by mutations in the laminin α2 gene (LAMA2). Of the more than 300 likely pathogenic variants found in the Leiden Open Variant Database, the majority are truncating mutations leading to complete LAMA2 loss of function, but multiple copy number variants (CNVs) have also been reported with variable frequency. We collected a cohort of individuals diagnosed with likely MDC1A and sought to identify both single nucleotide variants and small and larger CNVs via exome sequencing by extending the analysis of sequencing data to detect splicing changes and CNVs. Standard exome analysis identified multiple novel LAMA2 variants in our cohort, but only four cases carried biallelic variants. Since likely truncating LAMA2 variants are often found in heterozygosity without a second allele, we performed additional splicing and CNV analysis on exome data and identified one splice change outside of the canonical sequences and three CNVs, in the remaining four cases. Our findings support the expectation that a portion of MDC1A cases may be caused by at least one CNV allele and show how these changes can be effectively identified by additional analysis of existing exome data. Exome sequencing analysis can identify both novel single nucleotide variants (SNVs) and copy number variants (CNVs) in LAMA2 in congenital muscular dystrophy cases. When only one SNV allele is found, additional CNV analysis can provide a full genetic diagnosis.