Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing.,European Journal of Human Genetics

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Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing.
European Journal of Human Genetics ( IF 3.7 ) Pub Date : 2020-01-09 , DOI: 10.1038/s41431-019-0567-2
Ivana Jedličková ₁ , Maxime Cadieux-Dion _{2,

3} , Anna Přistoupilová ₁ , Viktor Stránecký ₁ , Hana Hartmannová ₁ , Kateřina Hodaňová ₁ , Veronika Barešová ₁ , Helena Hůlková _{1,

4} , Jakub Sikora _{1,

4} , Lenka Nosková ₁ , Dita Mušálková ₁ , Petr Vyleťal ₁ , Jana Sovová ₁ , Patrick Cossette ₂ , Eva Andermann ₅ , Frederick Andermann ₅ , Stanislav Kmoch ₁ ,

Affiliation

Adult-onset neuronal ceroid lipofuscinoses (ANCL, Kufs disease) are rare hereditary neuropsychiatric disorders characterized by intralysosomal accumulation of ceroid in tissues. The ceroid accumulation primarily affects the brain, leading to neuronal loss and progressive neurodegeneration. Although several causative genes have been identified (DNAJC5, CLN6, CTSF, GRN, CLN1, CLN5, ATP13A2), the genetic underpinnings of ANCL in some families remain unknown. Here we report one family with autosomal dominant (AD) Kufs disease caused by a 30 bp in-frame duplication in DNAJC5, encoding the cysteine-string protein alpha (CSPα). This variant leads to a duplication of the central core motif of the cysteine-string domain of CSPα and affects palmitoylation-dependent CSPα sorting in cultured neuronal cells similarly to two previously described CSPα variants, p.(Leu115Arg) and p.(Leu116del). Interestingly, the duplication was not detected initially by standard Sanger sequencing due to a preferential PCR amplification of the shorter wild-type allele and allelic dropout of the mutated DNAJC5 allele. It was also missed by subsequent whole-exome sequencing (WES). Its identification was facilitated by reanalysis of original WES data and modification of the PCR and Sanger sequencing protocols. Independently occurring variants in the genomic sequence of DNAJC5 encoding the cysteine-string domain of CSPα suggest that this region may be more prone to DNA replication errors and that insertions or duplications within this domain should be considered in unsolved ANCL cases.

中文翻译：

由 DNAJC5 重复引起的常染色体显性成人神经元蜡样脂褐质沉积症最初被桑格和全外显子组测序漏掉。

成人发病的神经元蜡样脂褐质沉积症（ANCL，库夫斯病）是一种罕见的遗传性神经精神疾病，其特征是蜡样物质在组织中溶酶体内积聚。蜡样积聚主要影响大脑，导致神经元损失和进行性神经变性。尽管已经确定了几个致病基因（DNAJC5、CLN6、CTSF、GRN、CLN1、CLN5、ATP13A2），但一些家族中 ANCL 的遗传基础仍然未知。在此，我们报道了一个患有常染色体显性遗传 (AD) Kufs 病的家系，该家族由编码半胱氨酸串蛋白 α (CSPα) 的 DNAJC5 中 30 bp 的框内重复引起。该变体导致 CSPα 半胱氨酸串结构域的中央核心基序重复，并影响培养的神经元细胞中棕榈酰化依赖性 CSPα 分选，类似于之前描述的两种 CSPα 变体 p.(Leu115Arg) 和 p.(Leu116del)。有趣的是，由于较短野生型等位基因的优先 PCR 扩增和突变 DNAJC5 等位基因的等位基因缺失，标准桑格测序最初并未检测到重复。随后的全外显子组测序（WES）也遗漏了这一点。通过重新分析原始 WES 数据以及修改 PCR 和桑格测序方案，促进了其鉴定。编码 CSPα 半胱氨酸串结构域的 DNAJC5 基因组序列中独立发生的变异表明，该区域可能更容易出现 DNA 复制错误，并且在未解决的 ANCL 病例中应考虑该结构域内的插入或重复。

更新日期：2020-01-09

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