Identification of compound heterozygous variants in the noncoding RNU4ATAC gene in a Chinese family with two successive foetuses with severe microcephaly.
Identification of compound heterozygous variants in the noncoding RNU4ATAC gene in a Chinese family with two successive foetuses with severe microcephaly.
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连续两胎严重小头畸形的中国家庭非编码 RNU4ATAC 基因复合杂合变异的鉴定
DOI：
10.1186/s40246-018-0135-9
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发表时间：
2018-01-25
期刊：
影响因子：
4.5
通讯作者：
Chen JM
中科院分区：
文献类型：
--
作者：
Wang Y;Wu X;Du L;Zheng J;Deng S;Bi X;Chen Q;Xie H;Férec C;Cooper DN;Luo Y;Fang Q;Chen JM
在过去几年中，全外显子组测序（WES）越来越多地用于临床诊断。然而，其使用的一个缺陷是，它不可避免地无法检测出发生在非编码RNA基因内的致病变异。我们在中国一个家庭中鉴定非编码RNU4ATAC基因致病变异的经验就是一个恰当的例子，这个家庭中连续两例胎儿受到严重小头畸形的影响。这些胎儿在小头畸形和脑部异常方面表现出非常相似的表型；然而，由于缺乏其他特征性表型特征，无法做出准确诊断。鉴于在怀孕期间没有报告/发现外部致病因素，我们在先证者（即第二例受影响的胎儿）中寻找该表型的遗传原因。
对染色体异常和致病性拷贝数变异的检测结果为阴性。WES结果也是阴性。这些最初的失败促使我们考虑RNU4ATAC的潜在作用，RNU4ATAC是一个与小头畸形骨发育不良原发性侏儒症1型（MOPD1）有关的非编码基因，MOPD1是一种严重的常染色体隐性疾病，其特征为侏儒症、严重小头畸形和神经异常。随后对RNU4ATAC进行的靶向测序鉴定出复合杂合变异，其中一个是最常报道的MOPD1致病突变（51G>A），而另一个是新的29T>A变异。四条不同的证据线（正常人群中的等位基因频率、受影响核苷酸的进化保守性、在已知的MOPD1致病变异突变热点内出现以及对RNA二级结构的预测影响）使我们能够得出结论：29T>A是MOPD1的一个新的致病变异。
我们的研究结果凸显了WES在无法检测非编码RNA基因内变异方面的局限性，并为全基因组测序作为儿科医学的一线基因检测提供了支持。此外，在MOPD1致病变异的突变热点内鉴定出一个新的RNU4ATAC变异，进一步强化了U4atac的5′茎环结构在健康和疾病中的关键作用。最后，这项分析使我们能够为母亲的第三次怀孕提供产前诊断和遗传咨询，这是在遗传性RNU4ATAC变异背景下的首例此类报告。
Background:Whole-exome sequencing (WES) over the last few years has been increasingly employed for clinical diagnosis. However, one caveat with its use is that it inevitably fails to detect disease-causative variants that occur within noncoding RNA genes. Our experience in identifying pathogenic variants in the noncoding RNU4ATAC gene, in a Chinese family where two successive foetuses had been affected by severe microcephaly, is a case in point. These foetuses exhibited remarkably similar phenotypes in terms of their microcephaly and brain abnormalities; however, the paucity of other characteristic phenotypic features had made a precise diagnosis impossible. Given that no external causative factors had been reported/identified during the pregnancies, we sought a genetic cause for the phenotype in the proband, the second affected foetus.Results:A search for chromosomal abnormalities and pathogenic copy number variants proved negative. WES was also negative. These initial failures prompted us to consider the potential role of RNU4ATAC, a noncoding gene implicated in microcephalic osteodysplastic primordial dwarfism type-1 (MOPD1), a severe autosomal recessive disease characterised by dwarfism, severe microcephaly and neurological abnormalities. Subsequent targeted sequencing of RNU4ATAC resulted in the identification of compound heterozygous variants, one being the most frequently reported MOPD1-causative mutation (51G>A), whereas the other was a novel 29T>A variant. Four distinct lines of evidence (allele frequency in normal populations, evolutionary conservation of the affected nucleotide, occurrence within a known mutational hotspot for MOPD1-causative variants and predicted effect on RNA secondary structure) allowed us to conclude that 29T>A is a new causative variant for MOPD1.Conclusions:Our findings highlight the limitations of WES in failing to detect variants within noncoding RNA genes and provide support for a role for whole-genome sequencing as a first-tier genetic test in paediatric medicine. Additionally, the identification of a novel RNU4ATAC variant within the mutational hotspot for MOPD1-causative variants further strengthens the critical role of the 5' stem-loop structure of U4atac in health and disease. Finally, this analysis enabled us to provide prenatal diagnosis and genetic counselling for the mother's third pregnancy, the first report of its kind in the context of inherited RNU4ATAC variants.
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影响因子：
1.9
作者：
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影响因子：
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作者：
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通讯作者：
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RNU4ATAC基因中具有双重突变的微脑骨突出原始矮型I型I型。
影响因子：
3.5
作者：
Nagy R;Wang H;Albrecht B;Wieczorek D;Gillessen-Kaesbach G;Haan E;Meinecke P;de la Chapelle A;Westman JA
通讯作者：
Westman JA