What Is the Exact Contribution of PITX1 and TBX4 Genes in Clubfoot Development? An Italian Study

• Published in: Genes Vol. 13; no. 11; p. 1958
• Main Authors: Bianco, Anna Monica, Ragusa, Giulia, Di Carlo, Valentina, Faletra, Flavio, Di Stazio, Mariateresa, Racano, Costantina, Trisolino, Giovanni, Cappellani, Stefania, De Pellegrin, Maurizio, d'Addetta, Ignazio, Carluccio, Giuseppe, Monforte, Sergio, Andreacchio, Antonio, Dibello, Daniela, d'Adamo, Adamo P
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27-10-2022; MDPI
• Subjects: Child; Classification; Clubfoot; Clubfoot - genetics; DNA Copy Number Variations - genetics; Etiology; Families & family life; Feet; Foot diseases; Genes; Genotype & phenotype; Humans; Maternal & child health; Mutation; Orthopedics; Patients; Pediatrics; Single-nucleotide polymorphism; T-Box Domain Proteins - genetics; congenital talipes equinovarus; clubfoot; PITX1; TBX4; congenital malformation
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes13111958

Congenital clubfoot is a common pediatric malformation that affects approximately 0.1% of all births. 80% of the cases appear isolated, while 20% can be secondary or associated with complex syndromes. To date, two genes that appear to play an important role are
and
, but their actual impact is still unclear. Our study aimed to evaluate the prevalence of pathogenic variants in
and
in Italian patients with idiopathic clubfoot.
and
genes were analyzed by sequence and SNP array in 162 patients. We detected only four nucleotide variants in
, predicted to be benign or likely benign. CNV analysis did not reveal duplications or deletions involving both genes and intragenic structural variants. Our data proved that the idiopathic form of congenital clubfoot was rarely associated with mutations and CNVs on
and
. Although in some patients, the disease was caused by mutations in both genes; they were responsible for only a tiny minority of cases, at least in the Italian population. It was not excluded that other genes belonging to the same
axis were involved, even if genetic complexity at the origin of clubfoot required the involvement of other factors.