Shwachman‐Diamond syndrome characterized by metaphyseal dysplasia, pancreatic insufficiency, and pancytopenia is caused by biallelic mutations in SBDS . Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. Here, we report two unrelated patients with Shwachman‐Diamond syndrome who were shown to be compound heterozygotes for relatively frequent pathogenic alleles (the 258+2T>C allele and another allele composed of 183‐184TA>CT and 201A>G) using an established polymerase chain reaction sequencing assay with SBDS‐specific primers. Exome analysis of the patients showed discrepant results: 258+2T>C with variant allele frequency around 0.85, and no variants detected for the 183‐184TA>CT allele. Parental exome analysis of the two families further supported this notion. Confronted with two patients with an unexpected segregation pattern, we performed a transcriptome analysis of peripheral blood‐derived mRNA to demonstrate that the results were compatible with those obtained using SBDS‐specific PCR primers. Both alleles could be accounted for by gene conversion events. The diagnostic discrepancy can be accounted for by a decreased efficiency in the computational mapping of the reads with 183‐184TA>CT and 201A>G to the reference sequence of the SBDS locus during exome analysis. This report highlights the pitfall of exome analysis for genes with pseudogenes, such as SBDS and the alternative use of RNA‐seq is recommended to circumvent this problem.

中文翻译：

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用于诊断Shwachman-Diamond综合征的外显子组分析的不足：由于假基因SBDSP1而导致的误解。

Shwachman-Diamond综合征特征在于干骺端发育异常，胰腺功能不全，和全血细胞减少是通过在双等位基因的突变引起SBDS。之间的基因转换SBDS和假SBDSP1是主要原因。在这里，我们报告了两名不相关的Shwachman-Diamond综合征患者，他们被证明是相对杂合的较常见致病性等位基因（258 + 2T> C等位基因，另一等位基因由183-184TA> CT和201A> G组成） SBDS特异性引物的聚合酶链反应测序测定。患者的外显子组分析显示出不同的结果：258 + 2T> C，等位基因变异频率约为0.85，并且未检测到183-184TA> CT等位基因变异。两个家庭的父母外显子组分析进一步支持了这一观点。面对两名患有意外分离模式的患者，我们对外周血来源的mRNA进行了转录组分析，以证明结果与使用SBDS特异性PCR引物获得的结果相符。这两个等位基因可由基因转化事件解释。可以通过将183-184TA> CT和201A> G的读段计算映射到SNP的参考序列的效率降低来解决诊断差异。外显子组分析中的SBDS基因座。本报告强调了对具有伪基因的基因（例如SBDS）进行外显子组分析的陷阱，建议使用RNA-seq替代方法来避免此问题。