A novel CEP290 disease-causing variant identified in a patient with leber congenital amaurosis using a medical diagnostic panel sequencing

ABSTRACT

Background

This study aims to identify the underlying genetic cause of a Chinese patient with Leber congenital amaurosis (LCA).

Methods

Detailed clinical data and family history were collected. A medical diagnostic panel sequencing covering 4450 genes was conducted. Two candidate disease-causing mutations detected in CEP290 were then validated with Sanger sequencing and bioinformatic analysis. Reverse transcription polymerase chain reaction (RT-PCR) and cDNA sequencing were performed to understand the effect of the novel CEP290 mutation on CEP290 mRNA splicing.

Results

A five-month-old LCA patient with both parents was enrolled. Medical diagnostic panel sequencing revealed that the patient is a compound heterozygote for two potentially pathogenic CEP290 mutations. Among them, c.1666dupA (p.I556NfsX20) was previously reported and has a significant association with LCA phenotype. A novel CEP290 mutation (c.3310–1_3313delGCTTA) was confirmed in both the patient and her father. RT-PCR and cDNA sequencing confirmed that the novel mutation affects the CEP290 mRNA splicing and results in a complete skipping of exon 29. The frameshift resulted in an early stop codon and truncation of the mutant protein by 1371 amino acid residues (p.L1104fsX6).

Conclusions

Our report provided a new mutation to the spectrum of CEP290-related diseases. The data suggested that the c.3310–1_3313delGCTTA mutation affects the CEP290 mRNA splicing and the CEP290 protein function. This valuable information is important for future studies on the mRNA splicing of CEP290 and the pathogenesis of CEP290-related diseases.

KEYWORDS:

• CEP290
• leber congenital amaurosis (LCA)
• next-generation sequencing (NGS)
• genotype-phenotype

Supplemental data

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

Acknowledgments

The authors thank the family members for their participation.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

B.C and Z.Z conceived and designed the study. B.C, Y.H, and S.Y conducted patient recruitment, sample collection, and ophthalmic examinations; Y.Z conducted bioinformatics analyses and analyzed the data; Y.Z wrote the manuscript. Z.Z applied for funding support.

Additional information

Funding

This study was supported by the Zhejiang Traditional Chinese Medicine Scientific Researching Fund Project [2020ZB138], the Public Technology Application Research Project of Science and the Technology Department of Zhejiang Province [2017C34004], the Zhejiang Natural Science Foundation [LQ19H120010 and LY20H120009], and the National Natural Science Foundation of China [31751003, 81900816].