Genetic and Clinical Characterization of Early-Onset High Myopia With or Without Cataract Due to Biallelic P3H2 Variants

Purpose: Biallelic pathogenic variants in P3H2 have been established as a cause of autosomal-recessive early-onset high myopia (eoHM) with or without cataract. This study aimed to further delineate the genetic and clinical features of P3H2-associated eoHM in a large cohort. Methods: P3H2 variants were identified from the exome sequencing data of 17,045 unrelated probands with various ocular conditions. Potential biallelic pathogenic variants were prioritized according to bioinformatic prediction, allele frequency, and segregation analysis in accordance with American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Clinical data were summarized. Results: Seventeen pathogenic or likely pathogenic biallelic P3H2 variants, all previously unreported, were identified in 11 patients from 11 of 1351 eoHM families (0.81%) but none of 15,694 families without eoHM (P = 7.5 × 10−13). All patients had eoHM (mean spherical equivalent, −12.29 ± 2.56 diopters; age at diagnosis, 3.55 ± 1.64 years), with cataracts observed in 4 of 11 (36.4%). Cataracts in these four patients (age at detection, 4–16 years) appeared as superior/temporal peripheral opacities that could only be observed after full mydriasis. Cataract occurrence was not associated with variant type or location, but increased significantly with age in a pooled analysis of our cohort and published cases (P for trend < 0.001). Longitudinal follow-up revealed a paradoxical hyperopic shift despite continuous axial elongation. Fundus changes included tessellated fundus (C1; 7/11) and diffuse choroidal atrophy (C2; 4/11). Conclusions: Biallelic P3H2 variants represent relatively common causes of autosomal-recessive eoHM, with a frequency comparable with LOXL3- and LRPAP1-associated eoHM. The distinct lens phenotype and refractive–axial dissociation are hallmarks of biallelic P3H2 variants.