The performance of international prenatal exome sequencing phenotyping criteria: a systematic review and comparative diagnostic accuracy study with historical individual participant data

Objectives: To evaluate; (i) the performance of the NHS England (NHSE) criteria for prenatal exome sequencing (pES); (ii) the diagnostic yields within individual NHSE criteria; (iii) the NHSE diagnostic yield when one or multiple criteria were met; and (iv) the performance of the NHSE criteria compared to international criteria.

Methods: An online survey of 120 countries interrogated which countries offer pES and their criteria. The performance of five pre-defined phenotypic criteria to offer pES was tested on a virtual cohort of 1054 unselected structurally abnormal fetuses undergoing pES derived from a previously published meta-analysis. The performance of current and prior gene panels used for NHSE pES were also assessed against the unselected cohort. The sensitivity and false positive rate (FPR) of each set of criteria in relation to diagnostic yield were summarised with 95% confidence intervals (CI) and the area under the curve (AUC) was calculated.

Results: There were 261 respondents from 63 countries. Where deducible, in 81.8% (n=45/55) of countries surveyed pES was offered. Where stated, most cases were selected on a case-by-case basis dependent on fetal phenotype and likelihood of an association with a monogenic condition and not on set pre-determined phenotypic criteria (90.3%, n=28/31). The diagnostic yield of NHSE criteria when applied to all relevant cases for pES was 27.8% (n=69), with pooled sensitivity, FPR and AUC of 49.8% (95% CI 31.7-67.9), 19.3% (7.8-40.5) and 0.66 (0.53-0.74), respectively. The diagnostic yield was most optimal for isolated short-long bones; 58.3% (n=7/12) and the likelihood of a monogenic diagnosis didn’t increase as the number of NHSE criteria met increased. There was a significant increase in the diagnostic yield of the current (2024) versus original (2019) gene panel for NHSE; 129/135 (95.6%) vs. 118/135 (87.4%) (p=0.017). The other four phenotypic criteria performed moderately well with the optimal performance seen for Canadian (British Columbia) criteria; pooled sensitivity 70.5% (43.7-88.1), FPR (10.9-62.5), and AUC 0.73 (0.59-0.79).

Conclusion: The majority of countries surveyed offer pES and do so on a case-by-case basis, dependent on fetal phenotype and likelihood of an underlying monogenic condition. Where known existing phenotypic criteria were compared, these performed modestly.