A novel mutation in the aspartate beta-hydroxylase (ASPH) gene is associated with a rare form of Traboulsi syndrome

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.

KEYWORDS:

• Genetic disorder
• Glaucoma
• DNA sequencing
• recessive inheritance
• mutation screening
• facial dysmorphism

Acknowledgments

We thank the patients and their families for their contribution.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Patient consent

The proband and his parents agreed to publish the proband’s image and case conditions.

Author contributions

Conceived the idea: SS, IK; Designed the study: IK; Patient recruitment SS; Sample collection: SSh, SV Performed the laboratory work: SSh, SV; Analysis of the data: SSh, SV, IK; In-Silico work: SSh, IK Wrote the initial draft of the paper: SSh, SV, IK, SS; Supervised the entire work: IK All authors viewed and contributed to the final paper.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This work has been supported by research grant to I.K. by the DST SERB, Ministry of Science and Technology, Government of India (EMR/2016/006979), and Hyderabad Eye Research Foundation for the financial support].