A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family
A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family
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DOI：
10.1002/humu.23383
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发表时间：
2018-03-01
期刊：
影响因子：
3.9
通讯作者：
Somlo, Stefan
中科院分区：
文献类型：
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作者：
Besse, Whitney;Choi, Jungmin;Somlo, Stefan
对于孤立性多囊肝病 (PCLD)，有必要扩大突变检测和新基因发现，因为 50% 的病例在 7 个已发表的疾病基因中没有发现突变。我们调查了一个有五个受影响兄弟姐妹的家庭，通过全外显子组测序分析没有发现功能丧失变异。 SNP 基因分型和连锁分析将候选区域缩小到大约 8% 的基因组，其中包括两个已发表的彼此非常接近的 PCLD 基因：GANAB 和 LRP5。基于这些发现，我们重新评估了外显子组测序数据，并在 GANAB 外显子 24 剪接供体附近发现了一个新的内含子九碱基对缺失，该缺失最初被序列分析流程丢弃。我们使用小基因测定来证明这种缺失导致细胞系和原代人胆管细胞中外显子 24 的跳跃。这些发现促使基因组评估超出编码区，以增强 PCLD 中的突变检测，并避免连锁不平衡中其他基因的过早影响。
Expanded mutation detection and novel gene discovery for isolated polycystic liver disease (PCLD) are necessary as 50% of cases do not have identified mutations in the seven published disease genes. We investigated a family with five affected siblings for which no loss-of-function variants were identified by whole exome sequencing analysis. SNP genotyping and linkage analysis narrowed the candidate regions to similar to 8% of the genome, which included two published PCLD genes in close proximity to each other, GANAB and LRP5. Based on these findings, we re-evaluated the exome sequencing data and identified a novel intronic nine base pair deletion in the vicinity of the GANAB exon 24 splice donor that had initially been discarded by the sequence analysis pipelines. We used a minigene assay to show that this deletion leads to skipping of exon 24 in cell lines and primary human cholangiocytes. These findings prompt genomic evaluation beyond the coding region to enhance mutation detection in PCLD and to avoid premature implication of other genes in linkage disequilibrium.