Prenatally diagnosed cleft lip and palate: Prenatal findings, clinical outcomes, genetic results, and sequencing yield in isolated versus non‐isolated cases
Thomas P. Kishkovich, Gabriela F. Tessler, Meghan Angley, Yijia Zhang, Thomas A. Imahiyerobo, Sherelle L. Laifer‐Narin, Hong Ma, Lynn Simpson, Caitlin D. Baptiste, Jessica L. Giordano, Russell S. Miller, Ronald J. WapnerAbstract
Introduction
Cleft lip and palate (CLP) are common congenital disruptions of the orofacial cleft and are associated with numerous genetic conditions. This study examines prenatal findings, clinical outcomes, and genetic findings among prenatally diagnosed CLP, with a focus on the yield of next‐generation sequencing (NGS).
Methods
This was a retrospective cohort study of prenatally diagnosed CLP presenting to a tertiary‐care referral center between 2017 and 2024. Inclusion required pre‐/postnatal diagnostic genetic testing. Imaging findings, genetic diagnoses, and delivery and postnatal outcomes were compared between those with isolated CLP (iCLP) and CLP with additional anomalies (CLP+). t ‐tests, Wilcoxon rank‐sum test, chi‐square test, or Fisher's exact test were used as appropriate.
Results
A total of 57 pregnancies met inclusion criteria: 19 (33.3%) iCLP and 38 (66.7%) CLP+. Among CLP+, the most common additional prenatally detected anomalies were central nervous system (55.3%) and cardiac (52.6%). Groups had similar rates of termination and live birth (26.0% and 68.0% overall, respectively). Neonatal intensive care unit (NICU) admission was frequent at 70.6%, and similar between groups (50.0% iCLP vs. 81.8% CLP+, p = 0.11). Across the cohort, 21 (36.8%) pregnancies had reported findings from genetic testing, with 16 (28.1% of total cohort, 76.2% of those with genetic findings) possessing findings explanatory of CLP. CLP+ pregnancies were more likely to have explanatory genetic findings (36.8% vs. 10.5%, p = 0.04). Eleven of 16 (68.8%) likely causative findings were detected via karyotype/CMA. Among 29 patients with NGS, five (17.2%) had likely causative variants not detected by karyotype/CMA. NGS increased overall pathogenic diagnostic yield from 19.3% to 28.1% and diagnosed additional clinically relevant findings in three cases.
Conclusion
Postnatal outcomes were overall similar between groups, with high rates of NICU admission. While CLP+ had higher rates of genetic findings, all CLP had risk of genetic disorders. In cases with non‐causative karyotype/CMA, sequencing revealed explanatory diagnostic variants in one in six cases, increasing diagnostic yield by nearly 10%. We advocate for comprehensive prenatal imaging and diagnostic genetic evaluation, including sequencing, for all prenatal CLP cases.