ABSTRACT

Background

Traboulsi syndrome is a rare autosomal recessive genetic disorder. The present study aimed to identify the pathogenic variants in the ASPH gene responsible for a rare and unique presentation of Traboulsi syndrome associated with cardiac disorder.

Methodology

DNA was isolated from the blood samples from 3 clinically diagnosed Traboulsi syndrome patients (n = 3) after obtaining a prior-informed consent. All three had classical ocular and facial dysmorphic features, and two of them also had associated cardiac problems. Mutation screening was performed for the exons of ASPH gene by Sanger sequencing in these patients and 350 controls. Sequence data analysis was performed using Seqscape and insilico protein analysis by SIFT, PyMOL, and Dynamut softwares.

Results

A novel homozygous variant(c.1853 T > A) in exon 21 was identified by Sanger sequencing in two of the three cases while a known pathogenic variant in exon 25 was identified in the third proband. The novel nonsense variant in exon 21 results in a premature truncation of gene resulting in a protein of 543 amino acids. This variant is not reported in ExAC, dbSNP and 1000 genome databases. Both the patients harboring this novel variant, had a unique presentation of Traboulsi syndrome with cardiac dysfunction. In silico analysis predicted the mutation to affect the calcium-binding activity of the gene which might explain the associated cardiac dysfunction in these two patients.

Conclusion

The novel pathogenic mutation displayed a perfect genotype-phenotype correlation in two probands of Traboulsi syndrome with cardiac dysfunction.

中文翻译：

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天冬氨酸β-羟化酶（ASPH）基因的一种新突变与一种罕见的 Traboulsi 综合征有关

摘要

背景

Traboulsi 综合征是一种罕见的常染色体隐性遗传病。本研究旨在鉴定导致与心脏疾病相关的 Traboulsi 综合征罕见且独特表现的ASPH基因中的致病变异。

方法

在获得事先知情同意后，从 3 名临床诊断的 Traboulsi 综合征患者（n = 3）的血液样本中分离 DNA。三人都有典型的眼部和面部畸形特征，其中两人也有相关的心脏问题。通过Sanger测序对这些患者和350名对照者进行了ASPH基因外显子的突变筛查。使用 Seqscape 和insilico蛋白质分析通过 SIFT、PyMOL 和 Dynamut 软件进行序列数据分析。

结果

在三个病例中的两个病例中，通过 Sanger 测序鉴定了外显子 21 中的一种新的纯合变异（c.1853 T > A），而在第三个先证者中鉴定了外显子 25 中的已知致病性变异。外显子 21 中的新型无义变异导致基因过早截断，从而产生 543 个氨基酸的蛋白质。ExAC、dbSNP 和 1000 基因组数据库中未报告此变体。携带这种新型变异的两名患者都有独特的 Traboulsi 综合征和心功能不全的表现。计算机分析预测突变会影响基因的钙结合活性，这可能解释了这两名患者的相关心脏功能障碍。

结论

新的致病突变在两个患有心功能不全的 Traboulsi 综合征先证者中显示出完美的基因型-表型相关性。