Two sisters with microphthalmia and anterior segment dysgenesis secondary to a PAX6 pathogenic variant with clinically healthy parents: a case of gonadal mosaicism?

PURPOSE: Genetic analysis of two siblings with complex microphthalmia, with clinically healthy parents. STUDY DESIGN: Clinical and experimental. METHODS: The patients underwent a detailed ophthalmic evaluation, including visual acuity, fundus examination, gonioscopy, ultrasound examination, and optical coherence tomography. Lensectomy with anterior vitrectomy was conducted in both patients. Additionally, in patient p1, electroencephalography analysis was performed. Genetic analysis was carried out using array comparative genomic hybridization (aCGH) and whole exome sequencing (WES). Bidirectional Sanger sequencing was conducted for validation and segregation analysis of the identified variant in the family. RESULTS: The aCGH results were normal. The heterozygous PAX6 variant c.52G>C (p.Gly18Arg) was identified in the proband (p1) through WES analysis. Sanger sequencing of exon 5 of PAX6 confirmed the presence of the variant in the other affected sibling (patient p2) but did not allow for identification of the variant in the parents' DNA isolated from leukocytes and buccal cells. CONCLUSIONS: The description of the variant in PAX6 in two siblings with clinically healthy parents who are negative for the mutation in DNA from leukocytes and buccal cells represents the possibility of parental gonadal mosaicism. Detection of germ cell mosaicism in the parents is essential to provide genetic counseling to the family regarding the risk of reoccurrence. Furthermore, we also report a pathogenic variant in PAX6 that to our knowledge has not so far been reported in patients with partial aniridia and therefore broadens the spectrum of the variants associated with aniridia.