CMA-first, ES-on-demand for fetuses with absent/hypoplastic nasal bone: a real-world diagnostic pathway and outcomes in 362 fetuses

Background: Absent or hypoplastic nasal bones are typically detected by ultrasound at the first or second trimester, yet guidance on how to counsel patients about these findings and studies on the proportion attributable to genetic factors remain limited. Methods: A retrospective study was conducted on 362 fetuses (including 17 twin pregnancies) with isolate absent or hypoplastic nasal bone (NBA/NBH) or those with other structural abnormalities detected by ultrasound. Samples were mainly categorized into two groups: isolated (n=199) group and non-isolated (n=163) group. All cases underwent chromosomal microarray analysis(CMA); exome sequencing (ES) was offered to CMA-negative cases with persistent clinical suspicion or additional anomalies. Outcomes included diagnostic yields, variant classification, inheritance, and pregnancy decisions. A literature review of isolated NBA/NBH was performed for context. Results: CMA detected abnormalities in 17.4% (63/362), including aneuploidy 11.3% (41/362) and copy number variants(CNVs) 6.1% (22/362). Detection rates differed by subgroup: isolated 7.0% (14/199) vs non-isolated 30.1% (49/163), P<0.01. In non‑isolated subgroup, CMA‑positive findings were most frequently associated with NT(nuchal translucency)/lymphatic abnormalities. Among CMA-negative cases, ES identified reportable findings in 20.9% (9/43): isolated 26.7% (4/15) vs non-isolated 17.9% (5/28), P>0.05. Variants included de novo P/LP changes explaining complex phenotypes (e.g., ARID1B frameshift, STAG1 truncation) and incidental findings (e.g., GJB2, ALPL, COL1A2 ). Pregnancy decisions tracked variant classification and inheritance: most aneuploidies and de novo pathogenic/likely pathogenic(P/LP) CNVs led to termination; variants of uncertain significance(VUS) or inherited variants were more often continued. Literature review of isolated NBA/NBH showed aneuploidy 4.4% and total detection rates is 10.9% via generic inverse-variance method, comparable to the present isolated cohort (aneuploidy 2.5%, CNV 4.5%, total 7.0%). Conclusion: Aneuploidy is the predominant cause of fetal NBA/NBH. A CMA-first strategy yields clinically actionable diagnoses, particularly in non-isolated cases; ES provides a 20.9% incremental yield among CMA-negative fetuses without a significant isolated vs non-isolated difference. Findings support a pragmatic, resource-conscious pathway: CMA-first for all NBA/NBH, with ES considered after negative CMA based on clinical suspicion.