Genetic analysis in fetuses with isolated clubfoot: diagnostic insights and added value

TL;DR

This study finds that genetic testing in fetuses with isolated clubfoot can reveal pathogenic variants, but routine testing for DMPK is not recommended.

Contribution

The study provides diagnostic insights into the genetic yield of isolated clubfoot and evaluates the added value of specific genetic tests.

Findings

Pathogenic or likely pathogenic variants were identified in 9.8% of tested isolated clubfoot cases.

Testing for DMPK did not significantly increase diagnostic yield in isolated clubfoot cases.

Unsolicited findings were identified in three cases, highlighting challenges in result interpretation.

Abstract

This study evaluates the diagnostic genetic yield in fetuses sonographically suspect of having isolated clubfoot. We conducted a retrospective study on all fetuses with apparently isolated clubfoot on initial ultrasound, examined between January 2021 and December 2024. Clubfoot was classified as isolated when no additional structural anomalies were observed on initial imaging. Among 218 cases, 140 (64%) were classified as isolated. Prenatal genetic testing was performed in 64 of these cases (46%), of which 61 (95%) underwent both copy number variant (CNV) and single nucleotide variant (SNV) analysis. In 38 of the 61 (62%) cases targeted investigation of the DMPK gene was carried out too. Pathogenic or likely pathogenic causative variants were identified in six of the 61 (9.8%) pregnancies: two of the 26 tested (7.7%) with unilateral clubfoot and four of the 35 tested (11.4%) with bilateral clubfoot. These include SNVs in TRPV4, PTPN11, BBS2, and MED13L (4/61 = 6.6%) and two CNVs, a de novo 22q11.23 deletion, and a de novo 5q21.1q31.1 deletion (2/61 = 3.3%). One case remained unsolved due to the identification of a variant of uncertain significance (VUS) in PIEZO2. Three cases revealed unsolicited findings unrelated to the indication for testing. Our findings highlight the diagnostic yield of prenatal CNV- and SNV-testing in cases of suspected isolated clubfoot, but does not support systemic testing for DMPK. Although broad genetic testing can support diagnosis and counseling, challenges remain in interpreting results and managing unsolicited findings.