Identification of Novel and Recurrent FBN1 Gene Mutations in Two Unrelated Turkish Families with Isolated Ectopia Lentis: A Case Report with Insights from a Literature Review.

Introduction: This study aimed to identify the potential genetic defects underlying familial clustering of lens dislocation in two unrelated Turkish families, consistent with the clinical features of isolated ectopia lentis (IEL). The investigation seeks to determine whether the detected findings overlap with those observed in other syndromic conditions that present with lens dislocation. Additionally, a focused review of IEL within the scientific literature was conducted to contextualize the molecular and phenotypic spectrum associated with lens abnormalities. The results of this study are expected to contribute to a deeper understanding of the molecular basis of IEL and to enhance diagnostic precision, genetic counseling, and clinical management strategies for affected individuals. Case Presentation and Conclusion: Comprehensive family histories and clinical evaluations revealed lens dislocation and associated ocular manifestations without systemic abnormalities or extraocular features suggestive of connective tissue disorders. Whole-exome sequencing (WES) in affected individuals identified two heterozygous FBN1 missense variants. The first variant, ENST00000316623.5:c.2920C>T, which has been previously reported in the literature, is located within the TB5 domain and was identified in ten affected members of family 1. The second variant, ENST00000316623.5:c.7018T>C, located within the TB9 domain, was identified in a single affected individual from family 2 and is reported here for the first time in association with IEL. Segregation analysis demonstrated that both variants co-segregated with the ectopia lentis phenotype and were completely absent in unaffected family members as well as in WES data from 200 ophthalmologically normal in-house controls. Besides, our study focused review of the literature on FBN1-associated IEL revealed that approximately 66.7% of reported variants involve missense substitutions affecting cysteine residues. Our study further reinforces this pattern by identifying two rare FBN1 missense variants that co-segregate with the phenotype, thereby expanding the known mutational spectrum of IEL. These findings also underscore the phenotypic heterogeneity of IEL, as reflected by the variable age of onset among affected individuals, and emphasize the critical role of domain-specific cysteine-altering mutations in the pathogenesis of IEL.