Genetic diagnostic yield of prenatal testing for fetal central nervous system abnormalities: a phenotype-driven study in a large single-center cohort.
4 affiliations
- 1Department of Medical Genetics, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China.
- 2Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China.
- 3Department of Medical Genetics, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China. [email protected].
- 4Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100010, China. [email protected].
Abstract
Objective
To evaluate the diagnostic yield and clinical value of a phenotype-driven genomic testing strategy in fetuses with central nervous system (CNS) abnormalities.Methods
In this retrospective single-center study, 966 fetuses with CNS abnormalities detected by prenatal ultrasound and/or fetal magnetic resonance imaging were included. All cases underwent copy number variation sequencing (CNV-seq), while karyotyping and trio exome sequencing (trio-ES) were performed based on clinical indications and parental preference. Fetuses were stratified into isolated-single, isolated-complex, and non-isolated subgroups according to CNS involvement and extracranial abnormalities. Diagnostic yields were compared across phenotypic subgroups and common CNS phenotypes.Results
Among 966 fetuses with prenatal CNS abnormalities, pathogenic or likely pathogenic (P/LP) variants were identified in 12.63% of cases. CNV-seq had a diagnostic yield of 8.07% (78/966), while trio-ES had a diagnostic yield of 16.32% (70/429) and provided an additional 10.92% yield (44/403) following negative CNV-seq results. Diagnostic yield varied significantly across phenotypic subgroups, with a higher CNV-seq yield in non-isolated cases than in isolated cases (15.41% vs. 4.25%, P < 0.001), and a higher ES yield in isolated-complex cases than in isolated-single cases (32.56% vs. 9.20%, P < 0.001). After excluding mild isolated CNS anomalies, diagnostic yields increased to 15.60% for CNV-seq and 26.67% for ES. In the adjusted cohort, differences among the three subgroups remained significant for CNV-seq (P < 0.001) but not for ES (P = 0.156). Across phenotypes, major structural abnormalities demonstrated substantially higher diagnostic yields than mild or soft markers, with a clear severity-dependent increase observed in ventriculomegaly and head circumference reduction.Conclusion
Fetal CNS abnormalities show substantial genetic heterogeneity, and diagnostic yield is closely associated with prenatal imaging phenotypes. A phenotype-driven testing strategy may help prioritize genetic evaluation and improve prenatal counseling for fetuses with CNS abnormalities.
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BibTeX
@article{fu2026genetic,
title = {{Genetic diagnostic yield of prenatal testing for fetal central nervous system abnormalities: a phenotype-driven study in a large single-center cohort.}},
author = {Xinyu Fu and Wei Zhong and Zhengyang Yao and Huimin Gao and Fang Wang and Yan Liu and Yifan Liu and Kai Yang and Yousheng Yan and Chenghong Yin},
journal = {Human genomics},
year = {2026},
month = aug,
doi = {10.1186/s40246-026-01022-w},
url = {https://europepmc.org/article/MED/42958445},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Genetic diagnostic yield of prenatal testing for fetal central nervous system abnormalities: a phenotype-driven study in a large single-center cohort.
AU - Xinyu Fu
AU - Wei Zhong
AU - Zhengyang Yao
AU - Huimin Gao
AU - Fang Wang
AU - Yan Liu
AU - Yifan Liu
AU - Kai Yang
AU - Yousheng Yan
AU - Chenghong Yin
PY - 2026
DA - 2026/08/03
JO - Human genomics
DO - 10.1186/s40246-026-01022-w
UR - https://europepmc.org/article/MED/42958445
AB - Objective To evaluate the diagnostic yield and clinical value of a phenotype-driven genomic testing strategy in fetuses with central nervous system (CNS) abnormalities.Methods In this retrospective single-center study, 966 fetuses with CNS abnormalities detected by prenatal ultrasound and/or fetal magnetic resonance imaging were included. All cases underwent copy number variation sequencing (CNV-seq), while karyotyping and trio exome sequencing (trio-ES) were performed based on clinical indications and parental preference. Fetuses were stratified into isolated-single, isolated-complex, and non-isolated subgroups according to CNS involvement and extracranial abnormalities. Diagnostic yields were compared across phenotypic subgroups and common CNS phenotypes.Results Among 966 fetuses with prenatal CNS abnormalities, pathogenic or likely pathogenic (P/LP) variants were identified in 12.63% of cases. CNV-seq had a diagnostic yield of 8.07% (78/966), while trio-ES had a diagnostic yield of 16.32% (70/429) and provided an additional 10.92% yield (44/403) following negative CNV-seq results. Diagnostic yield varied significantly across phenotypic subgroups, with a higher CNV-seq yield in non-isolated cases than in isolated cases (15.41% vs. 4.25%, P < 0.001), and a higher ES yield in isolated-complex cases than in isolated-single cases (32.56% vs. 9.20%, P < 0.001). After excluding mild isolated CNS anomalies, diagnostic yields increased to 15.60% for CNV-seq and 26.67% for ES. In the adjusted cohort, differences among the three subgroups remained significant for CNV-seq (P < 0.001) but not for ES (P = 0.156). Across phenotypes, major structural abnormalities demonstrated substantially higher diagnostic yields than mild or soft markers, with a clear severity-dependent increase observed in ventriculomegaly and head circumference reduction.Conclusion Fetal CNS abnormalities show substantial genetic heterogeneity, and diagnostic yield is closely associated with prenatal imaging phenotypes. A phenotype-driven testing strategy may help prioritize genetic evaluation and improve prenatal counseling for fetuses with CNS abnormalities.
SN - 1473-9542
SN - 1479-7364
ER -