NAA10 polyadenylation signal variants cause syndromic microphthalmia
NAA10 polyadenylation signal variants cause syndromic microphthalmia
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DOI：
10.1136/jmedgenet-2018-105836
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发表时间：
2019-07-01
影响因子：
4
通讯作者：
Biesecker, Leslie G.
中科院分区：
文献类型：
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作者：
Johnston, Jennifer J.;Williamson, Kathleen A.;Biesecker, Leslie G.
NAA 10（c.471+ 2 T>A）是编码N-乙酰基转移酶10的基因，其单一变异体与伦茨小眼综合征相关。在这项研究中，我们的目的是确定致病性的X连锁小眼综合征的家庭变异。方法对3个X连锁小眼球综合征家系15例患者进行连锁分析、外显子组测序和靶基因测序。使用定量PCR和RNAseq评估了NAA 10中两种鉴定的变体的结果。结果家系1的遗传连锁分析支持Xq 27-q28上的一个候选区域，该区域包括NAA 10。外显子组测序鉴定了半合子NAA 10多聚腺苷酸化信号（PAS）变体chrX：153，195，397 T>C，c.* 43 A>G，与病害分离。来自家族2和3的受影响男性的靶向测序鉴定了不同的NAA 10 PAS变体，chrX：g.153，195，401 T>C，c.* 39A>G和chrX：g.153，195，400 T>C，c.* 40A>G。这三种变体都没有出现在gnomAD中。定量PCR和RNAseq显示受影响个体中NAA 10 mRNA水平降低和3 'UTR异常。在另外376名受影响的个体中进行的NAA 10靶向测序未能识别PAS中的变体。结论PAS变异是NAA 10相关综合征性小眼症中最常见的变异类型，提示RNA减少是这些变异导致小眼症/无眼症的分子机制。我们回顾了与孟德尔疾病相关的PAS中公认的变体，并仅确定了23种其他变体，表明NAA 10含有所有已知PAS变体的10%以上。我们假设PAS在其他基因中含有与孟德尔疾病相关的未识别的致病性变异。PAS的系统询问可以提高基因检测的产率。
Background A single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia. Methods Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq. Results Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3 ' UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS. Conclusion These data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.