Clinical diagnosis of presumed SOX2 gonadosomatic mosaicism

Abstract

Purpose: To describe a family with presumed SOX2 gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother.Methods: The family underwent comprehensive ophthalmic and physical examination. Variant detection was performed using trio exome analysis on peripheral leukocyte DNA from blood and saliva samples. Variant segregation analysis was performed using a custom panel NGS sequencing. An identified variant in the SOX2 gene was confirmed in the proband by Sanger sequencing.Results: We report an individual with bilateral microphthalmia, developmental delay, hearing loss, and dysmorphic features. Her mother was found to have asymptomatic forme fruste uveal coloboma affecting her anterior segment. Her father, aunt, and sisters were unaffected. Trio exome sequence analysis showed an apparent de novo heterozygous deletion in the proband, NM_003106.3:c.70_89del, NP_003097.1:p.(Asn24Argfs*65), classified as pathogenic. Testing of the other family members' peripheral blood and saliva was negative for this variant. The iris transillumination abnormalities in the proband's mother supports a gonadosomatic mosaicism scenario.Conclusions: The results from this family underscore the importance of performing detailed evaluations of the parents of apparently sporadically affected individuals with heritable ophthalmic disorders. The identification of mildly affected individuals could substantially alter recurrence risks.

Keywords: SOX2; gonadosomatic; microphthalmia; mosaicism; transillumination.

Figure 1.

Pedigree representing both parents, maternal aunt (identical twin sister) and children. The proband, indicated by the arrow, has complex microphthalmia and a heterozygous SOX2 c.70_89del variant. The mother has a presumed forme fruste coloboma and a dotted shading to denote suspected mosaicism.

Figure 2.

(a) Slit lamp image of the proband’s right eye, showing a vascularized microcornea and a shallow, formed anterior chamber. (b) Proband’s left anterior segment also has microcornea and a mild dyscoria (pupil notch at 3:30 hour). (c) Proband’s posterior segment could only be evaluated OS, showing a uveal coloboma around the optic disc. D) Presumed forme fruste coloboma in the proband’s mother, appearing as iris transillumination patches at 5 o’clock OD and 6 o’clock OS, as well as abnormal pupil dilation OS.

Figure 3.

(a) Coverage and alignment tracks in the IGV browser. No read with the 20-bp deletion was found the parents’ data. Sequences of mismatched bases are shown. The reads with mismatched CGGCGGC are expected to contain the 20 nucleotides deletion due to misalignment because of the repeat in the reference sequence. (b) Previously reported predicted SOX2 protein familial variants.