Maternal Mosaicism in SSBP1 Causing Optic Atrophy with Retinal Degeneration: Implications for Genetic Counseling

Abstract

Background: Optic atrophy-13 with retinal and foveal abnormalities (OPA13) (MIM #165510) is a mitochondrial disease in which apparent bilateral optic atrophy is present and sometimes followed by retinal pigmentary changes or photoreceptors degeneration. OPA13 is caused by heterozygous mutation in the SSBP1 gene, associated with variable mitochondrial dysfunctions. Results: We have previously reported a 16-year-old Taiwanese male diagnosed with OPA13 and SSBP1 variant c.320G>A (p.Arg107Gln) was identified by whole exon sequence (WES). This variant was assumed to be de novo since his parents were clinically unaffected. However, WES and Sanger sequencing further revealed the proband’s unaffected mother carrying the same SSBP1 variant with a 13% variant allele frequency (VAF) in her peripheral blood. That finding strongly indicates the maternal gonosomal mosaicism contributing to OPA13, which has not been reported before. Conclusions: In summary, we described the first case of OPA13 caused by maternal gonosomal mosaicism in SSBP1 . Parental mosaicism could be a serious issue in OPA13 diagnosis, and appropriate genetic counseling should be considered.

Figure 1

Retinal images. (A) Color fundus photography of our patient with OPA13 at 16, 23 and 27 years old. (B) Spectral domain-optical coherence tomography of the macula at 16, 23 and 27 years old, and autofluorescence imaging at 16 and 27 years old.

Figure 2

Family studies. (A) Sanger sequencing (left) and whole exome sequencing (right) of the patient and his parents. SSBP1 variant c.320G>A (p.Arg107Gln) was identified in the proband (first row), but equivocal in his mother (second row) using Sanger sequencing. Whole exome sequencing revealed a 13% of variant allele frequency of the patient’s mother. His father’s result is negative (third row). (B) Color fundus photography and spectral domain-optical coherence tomography of the macula of the parents are normal.