Molecular-genetic and clinical diagnosis in a patient with complex eye dysgenesis, which included optic nerve coloboma and slight iris structure abnormalities

   Associations of missense variants in the PAX6 gene with complex ocular phenotypes are in focus of the Genetic Epidemiology Laboratory. The report discusses the results of the molecular diagnosis of a unique clinical case of a combination of subnormal iris and severe optic nerve coloboma, as well as the details of the patient’s phenotype. The patient, a young woman of 29 y.o., with a referring diagnosis of congenital eye pathology and optic nerves partial atrophy was examined ophthalmologically and genetically. PAX6 gene Sanger sequencing, MLPA analysis of the 11p13 chromosome, and whole-exome sequencing (WES) were performed. Targeted sequencing revealed a missense variant in the PAX6 gene NM_000280.4(PAX6):c.341A>G p.(Asn114Ser) in a heterogenous state, qualified as a variant of undefined clinical significance. The variant was detected in a healthy mother. Later, the patient was found to have a missense variant in the MAB21L2 gene: NM_006439.5:c.134T>A p.(Val45Glu) in the heterozygous state. The variant was not present in a control cohort, pathogenicity prediction programs considered the variant as damaging. Heterozygous pathogenic variants of the MAB21L2 gene were described in patients with bilateral eye coloboma combined with skeletal anomalies or without them with an autosomal dominant type of inheritance. The variant was not detected in a healthy mother. Analysis of WES allowed a decision on the causality of the missense variant in the PAX6 gene in a complex case of an aniridia-like phenotype. In the diagnostic solution of complex PAX6-associated phenotypes, it is necessary to rely on additional data obtained from at least the variant segregation and exome analyses. Eventually the patient was diagnosed with colobomatous microphthalmia.

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