Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome.
Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome.
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病例报告：NIPBL 基因深部外显子区域的新型杂合同义变异在 Cornelia de Lange 综合征患者中产生非规范剪接供体
DOI：
10.3389/fgene.2022.1056127
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发表时间：
2022
影响因子：
3.7
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中科院分区：
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科尔内利亚德兰格综合征（CdLS）是一种具有显著遗传异质性的常染色体显性遗传病或X连锁遗传病。NIPBL基因的变体在60%的患者中负责CdLS。在此，我们报告的情况下，与CdLS患者表现出独特的面部特征，小头畸形，发育迟缓，生长迟缓。对该患者进行全外显子组测序，在NIPBL基因外显子40的深部区域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，预测其会改变mRNA剪接。为了验证预测，进行逆转录酶-聚合酶链反应。该变体激活了隐蔽剪接供体，产生NIPBL的短转录本。NIPBL基因第40外显子3′端缺失137 bp，插入多个提前终止密码子，改变了开放阅读框架。定量实时PCR分析显示，在患者中全长转录本的转录水平与改变的短转录本的转录水平之比为5：1，而不是1：1。这些发现可以解释相对温和的患者的表型，无论由于mRNA的移码的截短蛋白的功能丧失。据我们所知，这项研究是第一个报告的同义变异的深外显子区域的NIPBL基因负责CdLS。所鉴定的变体扩展了NIPBL基因的突变谱。此外，同义变异可能是致病性的，这在疾病的临床和遗传诊断中不应被忽视。
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.