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Abstract：
Wiedemann-Rautenstrauch syndrome (WDRTS) is an extremely rare autosomal recessive neonatal disorder. Currently, over 50 cases with variable phenotypes of WDRTS have been reported. In our cohort of prenatal and postnatal growth retardation, a female proband was found to have general growth retardation, neurocutaneous syndrome, and anemia. Karyotype test and array-CGH detected no obvious chromosomal aberrations. Trio-based whole-exome sequencing (Trio-WES) identified bi-allelic compound mutations in the coding sequence (CDS) of POLR3A gene (c.3342C > T, p.Ser1114 = and c.3718G > A, p.Gly1240Ser). For the mild anemia phenotype, the underlying causal genetic factors could be attributed to the compound heterozygous mutations in FANCA gene (c.2832dup, p.Ala945CysfsTer6 and c.1902 T > G, p.Asp634Glu). Mini-gene reporter assays revealed that the synonymous variant of POLR3A and the missense variant of FANCA could affect pre-mRNA splicing of each gene. For POLR3A, the synonymous mutation (c.3342C > T, p.Ser1114=) generated three types of aberrant isoforms. Therefore, the female patient was finally diagnosed as WDRTS caused by POLR3A. For FANCA, the missense variant (c.1902 T > G, p.Asp634Glu) disrupted the normal splicing between exon 21 and 22, and produced two types of abnormal isoforms, one carrying the 1902G and the other spliced between exon 21 and 23 to exclude exon 22. Network analysis showed that POLR3A and FANCA could be STRINGed, indicating both proteins might collaborate for some unknown functions. Current investigation would broaden the knowledge for clinicians and genetic counselors and remind them to interpret those synonymous or predicted \"benign\" variants more carefully.
摘要：
Wiedemann-Rautenstrauch综合征（WDRTS）是一种极为罕见的常染色体隐性遗传性新生儿疾病。目前,已经报道了超过50例具有可变表型的WDRTS.在我们的产前和产后生长迟缓队列中，一名女性先证者被发现有普遍的生长迟缓，神经皮肤综合征,和贫血。核型测试和阵列CGH检测未发现明显的染色体畸变。基于Trio的全外显子组测序（Trio-WES）鉴定了POLR3A基因编码序列（CDS）中的双等位基因化合物突变（c.332C>T，p.Ser1114=和c.3718G>A，p.Gly1240Ser)。对于轻度贫血表型，潜在的因果遗传因素可归因于FANCA基因的复合杂合突变(c.2832dup，p.Ala945CysfsTer6和c.1902T>G，p.Asp634Glu)。小基因报告基因分析显示，POLR3A的同义变体和FANCA的错义变体可能会影响每个基因的mRNA前剪接。对于POLR3A，同义突变(c.332C>T，p.Ser1114=）产生三种类型的异常同工型。因此,该女性患者最终被诊断为POLR3A引起的WDRTS。对于FANCA来说,错义变体(c.1902T>G，p.Asp634Glu）破坏了外显子21和22之间的正常剪接，并产生了两种类型的异常同工型，一个携带1902G，另一个在外显子21和23之间拼接以排除外显子22。网络分析表明，POLR3A和FANCA可以被拉伸，这表明这两种蛋白质可能合作一些未知的功能。目前的调查将扩大临床医生和遗传咨询师的知识，并提醒他们更仔细地解释这些同义或预测的“良性”变异。
