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

To examine the diagnostic yield of exome sequencing (ES) in singleton pregnancies with isolated fetal clubfoot.

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.

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.

Sonographic diagnosis of clubfoot, even isolated, increases the risk for monogenic syndromes. Exome sequencing should be an option for genetic investigation for such pregnancies.