CorneliadeLange综合征(CdLS)是一种常染色体显性遗传或X连锁遗传疾病,具有明显的遗传异质性。在60%的患者中,NIPBL基因的变体负责CdLS。在这里,我们报告了一例表现出独特面部特征的CdLS患者,小头畸形,发育迟缓,和生长迟缓。对患者进行了全外显子组测序,并在NIPBL基因外显子40的深层区域中鉴定出一种新的从头杂合同义变体(NM_133433.4:c。6819G>T,p.Gly2273=)。根据ACMG/AMP指南,该变体的临床意义尚不确定;然而,基于计算机模拟分析,预测会改变mRNA剪接。要验证预测,进行了逆转录酶-聚合酶链反应。这个变种激活了一个隐秘的剪接供体,生成NIPBL的短转录本。在NIPBL外显子40的3'端检测到137bp的丢失,它可能通过插入多个过早终止密码子来改变开放阅读框。定量实时PCR分析显示,患者中全长转录物的转录水平与改变的短转录物的转录水平的比率为5:1,而不是1:1。这些发现可以解释患者相对温和的表型,无论由于mRNA中的移码而导致的截短蛋白的功能丧失。据我们所知,这项研究首次报道了NIPBL基因的深外显子区域中负责CdLS的同义变体。鉴定的变体扩展了NIPBL基因的突变谱。此外,同义变异可能是致病的,在疾病的临床和基因诊断中不容忽视。
Cornelia de Lange syndrome (CdLS) is an autosomal dominant or X-linked genetic disease with significant genetic heterogeneity. Variants of the NIPBL gene are responsible for CdLS in 60% of patients. Herein, we report the
case of a patient with CdLS showing distinctive facial features, microcephaly, developmental delay, and growth retardation. Whole exome sequencing was performed for the patient, and a novel de novo heterozygous synonymous variant was identified in the deep region of exon 40 in the NIPBL gene (NM_133433.4: c. 6819G > T, p. Gly2273 = ). The clinical significance of the variant was uncertain according to the ACMG/AMP guidelines; however, based on in silico analysis, it was predicted to alter mRNA splicing. To validate the prediction, a reverse transcriptase-polymerase chain reaction was conducted. The variant activated a cryptic splice donor, generating a short transcript of NIPBL. A loss of 137 bp at the 3\' end of NIPBL exon 40 was detected, which potentially altered the open reading frame by inserting multiple premature termination codons. Quantitative real-time PCR analysis showed that the ratio of the transcription level of the full-length transcript to that of the altered short transcript in the patient was 5:1, instead of 1:1. These findings may explain the relatively mild phenotype of the patient, regardless of the loss of function of the truncated protein due to a frameshift in the mRNA. To the best of our knowledge, this study is the first to report a synonymous variant in the deep exon regions of the NIPBL gene responsible for CdLS. The identified variant expands the mutational spectrum of the NIPBL gene. Furthermore, synonymous variations may be pathogenic, which should not be ignored in the clinical and genetic diagnosis of the disease.