The importance of genome sequencing: unraveling SSBP1 variant missed by exome sequencing

ABSTRACT

Background

Single-stranded DNA-binding protein 1 (SSBP1) plays an essential role in mitochondrial DNA (mtDNA) replication and maintenance, as well as development of retina. Here, we describe the clinical findings and genetic basis of a family with two members affected with bilateral optic atrophy.

Materials and methods

Clinical data were retrospectively collected from an electronic medical record system. Genetic results were obtained using exome sequencing (ES) and genome sequencing (GS).

Results

A 36-year-old man presented with low vision in both eyes since early childhood, with a best-corrected visual acuity of 20/500 in both eyes. He exhibited generalized optic atrophy and diffuse retinal nerve fiber layer thinning without retinal degeneration in both eyes. The family history was consistent with autosomal dominant traits. ES was performed; however, we did not identify any pathogenic variants in the known dominant optic atrophy genes. Subsequently, GS was performed, and it revealed a novel heterozygous c.364A>G p.(Lys122Glu) variant in SSBP1. In silico prediction supported it as deleterious, while segregation analysis detected it in his affected mother and his unaffected sister. No foveopathy or retinal degeneration was observed in the patient’s family members.

Conclusions

We report a novel pathogenic heterozygous SSBP1 variant in a family with autosomal dominant optic atrophy and incomplete penetrance. Furthermore, we demonstrated that GS is advantageous over ES even for the discovery of coding variants, providing uniform coverage. Therefore, GS should be emphasized to improve the molecular diagnostic rate of inherited optic neuropathy.

KEYWORDS:

• SSBP1
• inherited optic neuropathy
• optic atrophy
• dominant optic atrophy
• incomplete penetrance
• genome sequencing

Disclosure statement

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

Data availability statement

Genome data that support the findings of this study are available on request from the corresponding author.

Additional information

Funding

This study was supported by the Korean Disease Control and Prevention Agency (Grant No. 2018-ER6902-02 and 2019-NG-051-01) and the National Research Foundation (NRF) of Korea grant funded by the Korean government (MSIT; No. 2020R1C1C1007965); National Research Foundation of Korea [2020R1C1C1007965]; Korea Disease Control and Prevention Agency [2018-ER6902-02,2019-NG-051-01]