Genetic studies in isolated bilateral clubfoot detected by prenatal ultrasound

Abstract Objective To evaluate the contribution of genetic investigations in case of isolated bilateral clubfoot detected by routine prenatal ultrasound. Pathogenic Copy Number Variations is about 3.9% in fetuses with isolated clubfoot (uni- or bilateral). We hypothesize that this rate could be higher in a homogenous group of fetuses with bilateral clubfoot. Methods This retrospective single-center study included all women referred to our fetal-medicine center between 2013 and 2020 after ultrasound detection of isolated bilateral clubfoot. Genetic counseling was offered in which the woman was offered an amniocentesis for CMA and targeted investigation for Prader-Willi Syndrome (PWS), Steinert’s disease and Spinal Muscular Atrophy (SMA). Results 34 women were referred, 18 of them consented to undergo genetic studies by amniocentesis (18/34; 52.9%). Pathogenic copy number variations (CNVs) were found in 2/18 (11.1%) of cases. One of these CNVs was directly linked to the clubfoot pathology (a deletion in 5q31.1 containing PITX1 gene). Four fetuses (4/18, 22.2%) had variants of unknown significance (VUS). No PWS, SMA or Steinert’s disease was found. No case diagnosed with isolated clubfoot prenatally had additional anomalies postnatally. Conclusions In the case of bilateral isolated clubfoot detected at the antenatal ultrasound, invasive prenatal testing should be offered, and if accepted, a CMA should be done, as pathogenic variations were observed in up to 11.1% of women who got amniocentesis. The findings of this study do not support the systematic recommendation of molecular studies for PWS, SMA, Steinert’s disease.

[1]  S. Demir,et al.  The relationship between isolated pes equinovarus and aneuploidies and perinatal outcomes: Results of a tertiary center , 2020, Turkish journal of obstetrics and gynecology.

[2]  L. Sagi‐Dain,et al.  Prenatal clubfoot increases the risk for clinically significant chromosomal microarray results - Analysis of 269 singleton pregnancies. , 2020, Early human development.

[3]  M. Brasseur-Daudruy,et al.  Clubfoot Versus Positional Foot Deformities on Prenatal Ultrasound Imaging , 2020, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[4]  A. Khalil,et al.  Outcome of isolated fetal talipes: A systematic review and meta‐analysis , 2019, Acta obstetricia et gynecologica Scandinavica.

[5]  Chunlei Liu,et al.  ClinVar: improving access to variant interpretations and supporting evidence , 2017, Nucleic Acids Res..

[6]  Daniel G. MacArthur,et al.  The ExAC browser: displaying reference data information from over 60 000 exomes , 2016, bioRxiv.

[7]  Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders , 2016, Obstetrics and gynecology.

[8]  N. Gruchy,et al.  Prenatal diagnosis of clubfoot: Chromosomal abnormalities associated with fetal defects and outcome in a tertiary center , 2016, Journal of clinical ultrasound : JCU.

[9]  Erik S. Wright,et al.  Using DECIPHER v2.0 to Analyze Big Biological Sequence Data in R , 2016, R J..

[10]  D. Levine,et al.  Correction to “AIUM: Consensus Report on the Detailed Fetal Anatomic Ultrasound Examination: Indications, Components, and Qualifications” , 2015 .

[11]  D. Levine,et al.  Consensus Report on the Detailed Fetal Anatomic Ultrasound Examination , 2014, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[12]  Matthew J. Silva,et al.  Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. , 2011, Human molecular genetics.

[13]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[14]  F. Malone,et al.  Isolated Clubfoot Diagnosed Prenatally: Is Karyotyping Indicated? , 2000, Obstetrics and gynecology.