Diverse PAX6 variants in three Chinese families with congenital aniridia: genotype–phenotype correlations and diagnostic implications

Abstract

To report three families with congenital aniridia harboring different types of PAX6 variants, analyze their genetic characteristics and genotype–phenotype correlations, and explore the value of a multi-technique combined detection strategy in the molecular diagnosis of aniridia. Systematic ophthalmic examinations were performed on the probands and their family members from three aniridia families. Genetic testing was conducted using multiple techniques including high-resolution chromosome karyotyping, array comparative genomic hybridization, whole-exome sequencing, Sanger sequencing, and quantitative real-time polymerase chain reaction. Variant pathogenicity was assessed according to the American College of Medical Genetics and Genomics/Clinical Genome Resource guidelines. Three pathogenic or likely pathogenic variants were identified in the respective families: Family 1 harbored a heterozygous deletion at 11p13, arr[GRCh37] 11p13(31037165_34227327) × 1 (∼3.19 megabases), encompassing PAX6 , WT1 , and several other genes, which occurred de novo ; Family 2 harbored a heterozygous frameshift variant in PAX6 , c.1234del (p.Ser412ProfsTer127) on the current MANE Select transcript NM_001368894.2, inherited maternally; Family 3 harbored a de novo large deletion at 11p14.1p13, seq[GRCh37] del(11)(p14.1p13) NC_000011.9:g.30352495_33350179del (∼2.998 megabases), also encompassing PAX6 , WT1 , and other genes. The two copy number variants were classified as pathogenic and the frameshift variant as likely pathogenic according to the American College of Medical Genetics and Genomics/Clinical Genome Resource standards. This study reports three different types of pathogenic or likely pathogenic PAX6 variants, enriching the variant spectrum of aniridia. The combined application of array comparative genomic hybridization, whole-exome sequencing, and Sanger sequencing can significantly improve the molecular diagnostic rate of aniridia. The deletion regions in Families 1 and 3 both encompass the WT1 gene, meeting the molecular diagnostic criteria for WAGR syndrome. Notably, the proband of Family 3 had been diagnosed with Wilms tumor prior to presentation, underscoring the importance of precise genetic diagnosis for clinical management and genetic counseling.