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

Vollständiger Abstract

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ABSTRACT 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.