Prenatal isolated clubfoot increases the risk for clinically significant exome sequencing results

Objective To examine the diagnostic yield of exome sequencing (ES) in singleton pregnancies with isolated fetal clubfoot. Methods Clinical data from singleton pregnancies with a sonographic diagnosis of isolated clubfoot and ES results between 2018 and 2021 were retrospectively obtained from a single referral medical center. The recorded data include maternal age, gestational age at sonographic diagnosis, the indication for genetic testing, ES results, and pregnancy outcomes. Results During the study period, 38 fetuses were prenatally diagnosed with isolated clubfoot by ultrasound and underwent ES after the copy number variant analysis was non‐diagnostic. Through the trio‐ES analysis, pathogenic or likely pathogenic variants were detected in 4 of 38 (10.5%) with the following genes: BRPF1, ANKRD17, FLNA, and KIF1A. All are de novo with three of autosomal dominant inheritance and one of X‐linked recessive inheritance. Conclusion Sonographic diagnosis of clubfoot, even isolated, increases the risk for monogenic syndromes. Exome sequencing should be an option for genetic investigation for such pregnancies. Key points What's already known about this topic? Clubfoot is one of the common congenital anomalies detected prenatally. The prognosis depends on whether it is associated with additional malformations. The use of chromosomal microarray analysis (CMA) to identify the genetic etiology of isolated fetal clubfoot has been recommended. What does this study add? Sonographic diagnosis of fetal isolated clubfoot can increase the risk for single gene disorders. Exome sequencing (ES) should be an option for genetic investigation in such pregnancies.