Multimodal genomic testing in prenatal diagnosis: incremental diagnostic contribution of chromosomal microarray and exome sequencing, real-world NIPT confirmation rates and pregnancy outcomes in 120 consecutive amniocenteses from northeastern Türkiye — a retrospective cohort study

Abstract

Most evidence on chromosomal microarray analysis (CMA) and exome sequencing (ES) in prenatal diagnosis comes from high-volume centres. We evaluated the incremental diagnostic contribution of additional testing modalities, non-invasive prenatal testing (NIPT) confirmation rates and pregnancy outcomes at a regional centre in Türkiye. Retrospective cohort of 120 consecutive amniocenteses (March 2022–June 2025). The pathway was retrospectively observed, not uniformly implemented: the intended first-tier panel (quantitative fluorescent PCR, G-banded chromosome analysis, CMA) was completed in 94 pregnancies (78.3%), CMA in 101 (84.2%); ES (n = 13) and targeted testing (n = 25) were selective. Findings were classified before analysis as fetal disease-causing or incidental/non-diagnostic. Cumulative yields use the whole cohort as denominator. Abnormal findings occurred in 36 of 120 pregnancies (30.0%): 27 (22.5%) disease-causing and 9 (7.5%) incidental/non-diagnostic — 3 heterozygous pathogenic or likely pathogenic variants in autosomal recessive genes (2.5%) and 6 variants of uncertain significance (VUS; 5.0%). Disease-causing yield rose from 16.7% to 22.5%: seven of the 27 diagnoses were first identified by CMA, ES or targeted testing, a cohort-specific contribution, not a diagnostic yield, as these modalities were not applied uniformly. Abnormal ultrasonography was associated with an abnormal genetic finding (31/83 vs. 5/37; unadjusted OR 3.82, 95% CI 1.35–10.82); not significant for disease-causing findings alone. Within this referral stream, confirmation of 14 high-risk NIPT referrals was 6/6 for trisomies 21 and 18, 0/4 for sex chromosome and rare autosomal aneuploidies and 1/4 for copy-number variants; these should not be read as population-level positive predictive values. Outcome, sought only after an abnormal finding, was documented in 30 of 36; 22 were terminated (trisomy 18, 4/4; isolated VUS, 1/6). CMA, ES and targeted testing added diagnoses in a non-uniformly applied pathway (complete first-tier panel in 78.3%). The findings reinforce the importance of diagnostic confirmation of high-risk NIPT results before irreversible clinical decisions, particularly for less common targets, which were frequently not confirmed in this referral series. Termination frequencies varied across diagnostic categories; these descriptive differences should be considered in the context of the underlying fetal phenotype, diagnostic certainty, and parental preferences when counselling is provided.