A Novel Pathogenic Variant in PAX2‐Related Renal Coloboma Syndrome Identified by Prenatal Diagnosis: A Case Report and Literature Review

Abstract

Introduction Renal coloboma syndrome (RCS) is an autosomal dominant disorder caused by pathogenic variants in the PAX2 gene, primarily affecting renal and optic nerve development. However, the presentation of RCS is highly heterogeneous, ranging from mild renal anomalies to severe multi‐organ involvement. This phenotypic variability often poses significant challenges for accurate clinical diagnosis. Case Presentation In this study, a novel heterozygous PAX2 missense mutation (NM_000278.5: c.404 T > G, p.Ile135Ser) was identified via whole‐exome sequencing (WES) in a 31‐year‐old pregnant woman and her fetus. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this mutation is classified as likely pathogenic. The phenotypic divergence observed between the mother and neonate underscores the syndrome′s variable penetrance. While the mother exhibited relatively mild renal and optic nerve anomalies, the neonate presented with severe multi‐organ involvement, including renal structural defects, hearing impairment, and extensive pulmonary, cardiac, and cerebral lesions, culminating in fatal intracranial hemorrhage and multi‐organ failure at 2 months of age. Discussion The present case identified a previously unreported pathogenic variant in the PAX2 gene, thereby expanding the mutational spectrum of PAX2‐related RCS. It also further underscores the phenotypic heterogeneity of this disorder, even among members of the same family. Additionally, the genotype–phenotype spectrum of PAX2‐related cases was also reviewed to facilitate early diagnosis, management, and genetic counseling for RCS.