Genomic Profiling of Anophthalmia/Microphthalmia‐Associated CNVs Reveals Complex Genotype–Phenotype Correlations and Incomplete Penetrance

BACKGROUND: Anophthalmia/microphthalmia (A/M) is a severe congenital ocular malformation characterized by the complete absence or small size of the eye bulb. Interpreting copy number variations (CNVs) in A/M is challenged by variable genotype-phenotype correlations and reduced penetrance. This study investigated the genetic etiology of A/M-associated CNVs. METHODS: Genomic profiling was performed on four unrelated families presenting with ocular anomalies or harboring A/M-susceptible CNVs. Variants were evaluated by integrating American College of Medical Genetics and Genomics (ACMG) guidelines with clinical phenotypes and familial segregation. RESULTS: An inherited 8.13 Mb deletion (8p23.3p23.1) in Patient 1 was excluded due to genotype-phenotype mismatch. Patients 2 and 3 harbored de novo pathogenic deletions involving OTX2 (14q22.3) and SOX2 (3q26.33), causing typical A/M. Case 4 revealed a 14q22.2q23.1 deletion encompassing OTX2 in a fetus and mother without ocular anomalies, consistent with the incomplete penetrance of OTX2-related microphthalmia. Thus, CNV-induced haploinsufficiency causes A/M with high phenotypic variability. CONCLUSION: Accurate CNV interpretation requires robust genotype-phenotype correlation and careful assessment of incomplete penetrance to prevent diagnostic pitfalls and improve genetic counseling.