(540) Pathogenic and likely pathogenic copy number variants detected by chromosomal microarray in isolated fetal ventriculomegaly

Rich data exist on genomic changes in fetuses with non-isolated structural abnormalities. However, for isolated ventriculomegaly (VM) they are still inconsistent and heterogenous, making parental decision difficult regarding further invasive testing.

The aim of this project was to perform qualitative and quantitative assessment of the current evidence on the prevalence of pathogenic and likely pathogenic (P/LP) copy number variants (CNVs) in fetuses with apparently isolated VM and normal karyotype.

Study Design:

A systematic review of studies reporting on the prevalence of P/LP CNVs detected by chromosomal microarray (CMA) in fetal isolated VM from inception to December 2024 was conducted. Synthesis was performed separately for data on all isolated VM ≥10mm and for data on non-severe isolated VM ≥10mm and ≤15mm.  For quantitative assessment the extracted results were pooled in a meta-analysis of proportions and presented using forest plots. Heterogeneity was assessed using Higgins’ I2. PROSPERO CRD42021279656

Results:

Twenty two studies incorporating in total n=2999 cases with isolated VM and normal karyotype (CNVs >10Mb excluded) were included in the final meta-analyses. For all isolated VM ≥10mm (n=1967) the incremental yield of P/LP CNVs was 5% (95% CI 3-7%; I2=69.06%) (Fig 1.), and for non-severe isolated VM (≥10mm and ≤15mm; n=1561) the incremental yield of P/LP CNVs was 3% (95% CI 1-5%; I2=66.5%) (Fig 2). Synthesis was attempted in mild (≥10mm and ≤12mm) and severe ( >15mm) VM groups but ultimately not performed due to the lack of adequate data.

Conclusion:

This study provides the clarity for counselling patients with fetal isolated VM and isolated non-severe VM. Original separate data is scarce for mild and severe VM groups. While severe VM is likely to have a guarded prognosis even in cases where genetic cause is not found, having more specified data on the prevalence of genetic changes in mild VM (≥10mm and ≤12mm) would have the potential to transform the counselling in Fetal Medicine setting. Further original data need to be collected to be able to advise patients accordingly.