Molecular and Clinical Analyses of 111 Patients with Bilateral Anterior-Segment Dysgenesis/Aniridia and Microphthalmia/Anophthalmia.

De novo variants in PAX6, PITX2 or GJA8 and parentally derived variants in FOXC1 and CYP1B1 for anterior-segment dysgenesis; ABCB6, BMP4 and OTX2 variants predominantly inherited for microphthalmia or anophthalmia.

One hundred and eleven patients and their family members with bilateral ocular lesions were recruited in a Japanese multicenter collaborative study, with next-generation sequencing on custom panels of 11 and 12 major causative genes for anterior-segment dysgenesis with aniridia and for microphthalmia or anophthalmia respectively. Genetic diagnosis rates were 50.0% for anterior-segment dysgenesis with aniridia and 37.5% for microphthalmia or anophthalmia, and eleven previously unreported variants were identified. De novo variants in PAX6, PITX2 or GJA8 and parentally derived variants in FOXC1 and CYP1B1 were the major causes of anterior-segment dysgenesis with aniridia, whereas ABCB6, BMP4 and OTX2 variants associated with microphthalmia or anophthalmia were predominantly inherited from parents with no or different ocular phenotypes. The authors report a high incidence of glaucoma in patients with CYP1B1 and FOXC1 variants, frequent systemic abnormalities with FOXC1 and PITX2, and neurologic abnormalities associated with BMP4 and RARB variants, and conclude that phenotypes such as Peters anomaly and Axenfeld anomaly belong to a single, genetically heterogeneous spectrum that may overlap with aniridia.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

What is worth keeping from this series is not the panel yield, around 50% and 37.5%, but the map of complications by gene: glaucoma with CYP1B1 and FOXC1, systemic involvement with FOXC1 and PITX2, neurologic involvement with BMP4 and RARB. That information directly organizes a child's follow-up once the result is returned, and justifies genetic analysis beyond diagnostic labelling alone. The frequent parental transmission of microphthalmia or anophthalmia variants from unaffected or differently affected parents is the second practical message, to be built into genetic counselling and ophthalmological examination of relatives.

Analysis by Dr Thibaut Benquey