Introduction

As prenatal diagnostic techniques advance, whole exome sequencing (WES) is increasingly applied to detect genetic anomalies in fetuses exhibiting structural abnormalities. However, this progress comes with challenges, particularly when variants of uncertain significance (VUS) are identified in genes tied to critical phenotypes.

Case Report

In a notable case, a couple undergoing their third in vitro fertilization (IVF) attempt faced a heartbreaking scenario at 24 + 6 weeks of gestation when an ultrasound revealed significant anomalies in their fetus, including polydactyly and the 'molar tooth sign,' indicative of Joubert syndrome. A subsequent Trio-based WES analysis conducted on the parents and the affected fetus uncovered compound heterozygous variants in the CPLANE1 gene, specifically c.4646 A>T (p.Glu1549Val) and c.1233 C>A (p.Tyr411*). While one variant was deemed pathogenic, the other was classified as VUS according to the American College of Medical Genetics and Genomics (ACMG) guidelines.

Intriguingly, these variants were found to have no Allele frequencies in the general population, raising further questions. Bioinformatic predictions suggested that the p.E1549V variant may adversely affect protein function due to its location in a highly conserved region, highlighting the complexity of interpreting such findings. Since CPLANE1 is primarily expressed during fetal development, particularly in the brain, these variants’ potential contributions to the observed anomalies were considered significant by the medical team. Ultimately, the couple made the heart-wrenching decision to terminate the pregnancy.

Challenges in Prenatal Diagnosis

The case illustrates the difficulties inherent in prenatal genetic counseling, especially when parents are confronted with VUS linked to potentially severe conditions. The prevalence of fetal structural anomalies ranges widely, with estimates between 2-4% per pregnancy, leading to critical implications for parents as they navigate difficult reproductive decisions. While WES improves diagnostic yield (between 8.5 to 35%), the discovery of VUS complicates counseling, often provoking heightened anxiety among parents without clear clinical benefit.

Biallelic variants in the CPLANE1 gene have been previously associated with Joubert syndrome, characterized by specific malformations, including cerebellar dysplasia. However, variant interpretation remains challenging. Changes in the genetic landscape, including VUS status, necessitate a deeper understanding of the associated phenotypic implications over time. This complexity calls for comprehensive genetic resources and support systems for those facing similar decisions.

Broader Implications

Past literature suggests that VUS, particularly in clinically significant genes, may foreshadow future familial complexities and potential health outcomes for subsequent pregnancies. In this study, the absence of the identified variants in population databases underscores their potential roles in pathogenesis. The limitations inherent in prenatal diagnosis—from ambiguous imaging results to the lack of postmortem genetic evaluation—highlight a pressing need for improved protocols in genetic research and fetal medicine.

Conclusion

This case reinforces the argument for integrating genetic findings with robust clinical analysis in the prenatal diagnosis of Joubert syndrome and similar conditions. With evidence pointing to the potential pathogenicity of the identified CPLANE1 variants, further research is essential in establishing clearer frameworks for interpreting VUS. Ongoing discussions around genetic counseling and prenatal care must emphasize the psychological impact of these diagnoses, guiding families through their reproductive choices with compassion and clarity. This evolving field warrants continuous exploration, as molecular insights pave the way for enhanced understanding and support for families navigating the complexities of prenatal genetic diagnosis.