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NAT2 variation and idiopathic talipes equinovarus (clubfoot).Hecht JT, Ester A, Scott A, Wise CA, Iovannisci DM, Lammer EJ, Langlois PH, Blanton SH. Am J Med Genet A. 2007 Aug 28;
Idiopathic talipes equinovarus (ITEV), or isolated clubfoot, is a common developmental anomaly that is characterized by a rigid foot, adducted forefoot, cavus midfoot, equinovarus of the hindfoot, and hypoplastic calf musculature. The etiology of this common birth defect is largely unknown, but genetic factors have been implicated in population and family studies and maternal smoking during pregnancy has been identified as an environmental risk factor. The biotransformation of exogenous substances, such as tobacco smoke, is modulated by numerous genes including N-acetylation genes, NAT1 and NAT2. Functional variants of these genes exist and can be distinguished by genotyping. We hypothesized that variation in NAT1 and NAT2 genes might be associated with ITEV. To test this hypothesis, NAT1 and NAT2 were genotyped in a sample of 56 multiplex ITEV families, 57 trios with a positive family history and 160 simplex trios with ITEV. The results detected a slight decrease in the expected number of homozygotes for the NAT2 normal allele in the Hispanic simplex trios. In addition, in a pilot case-control study of ITEV, there were significantly more slow NAT2 acetylators among the cases. This suggests that slow acetylation may be a risk factor for ITEV. This study is the first to find evidence suggesting a role for a biotransformation candidate gene in the etiology of ITEV and provides a scientific foundation to further explore the contributions of other tobacco metabolism genes in the etiology of clubfoot.
Is there evidence for aetiologically distinct subgroups of idiopathic congenital talipes equinovarus? A case-only study and pedigree analysis.
Cardy AH, Sharp L, Torrance N, Hennekam RC, Miedzybrodzka Z. PLoS One. 2011 Apr 20;6(4):e17895.
Idiopathic congenital talipes equinovarus (CTEV) is a common developmental foot disorder, the aetiology of which remains largely unknown. Some aspects of the epidemiology suggest the possibility of aetiologically distinct subgroups. Previous studies consider CTEV as a homogenous entity which may conceal risk factors in particular subgroups. We investigate evidence for aetiologically distinct subgroups of CTEV.
Parents of 785 probands completed a postal questionnaire. Family pedigrees were compiled by telephone. Case-only analysis was used to investigate interactions between risk factors and sex of the proband, CTEV laterality and CTEV family history.
The male∶female ratio was 2.3∶1, 58% of probands were affected bilaterally and 11% had a first-second degree family history. There were modest interactions between family history and twin births (multivariate case - only odds ratio [ORca] = 3.87, 95%CI 1.19-12.62) and family history and maternal use of folic acid supplements in early pregnancy (ORca = 0.62, 95%CI 0.38-1.01); and between sex of the proband and maternal alcohol consumption during pregnancy (female, positive history and alcohol consumed: ORca = 0.33, 95%CI 0.12-0.89). Previous reports of an interaction between maternal smoking and family history were not confirmed. Relatives of female probands were affected more often than relatives of male probands.
These results provide tentative evidence for aetiologically distinct CTEV subgroups. They support the 'Carter effect', suggesting CTEV develops though a multifactorial threshold model with females requiring a higher risk factor 'load', and suggest areas where future aetiological investigation might focus. Large multi-centre studies are needed to further advance understanding of this common condition.
Modern advances in genetics have allowed investigators to identify the complex etiology of clubfoot. It has become increasingly apparent that clubfoot is a heterogeneous disorder with a polygenetic threshold model explaining its inheritance patterns. Several recent genetic studies have identified a key developmental pathway, the PITX1-TBX4 transcriptional pathway, as being important in clubfoot etiology. Both PITX1 and TBX4 are uniquely expressed in the hindlimb, which helps explain the foot phenotype seen with mutations in these transcription factors. Future studies are needed to develop animal models to determine the exact mechanisms by which these genetic abnormalities cause clubfoot and to test other hypotheses of clubfoot pathogenesis.
Studies of TBX4 and chromosome 17q23.1q23.2: An uncommon cause of nonsyndromic clubfoot.
Lu W, Bacino CA, Richards BS, Alvarez C, Vandermeer JE, Vella M, Ahituv N, Sikka N, Dietz FR, Blanton SH, Hecht JT. Am J Med Genet A. 2012 Jun 7.
Clubfoot is a common birth defect characterized by inward posturing and rigid downward displacement of one or both feet. The etiology of syndromic forms of clubfoot is varied and the causes of isolated clubfoot are not well understood. A microduplication of 2.2 Mb on chromosome 17q23.1q23.2 which includes T-box 4 (TBX4), a hindlimb-specific gene, and 16 other genes was recently identified in 3 of 66 families reported as nonsyndromic clubfoot, but additional non-foot malformations place them in the syndromic clubfoot category. Our study assesses whether variation in or around TBX4 contributes to nonsyndromic clubfoot. To determine whether this microduplication was a common cause of nonsyndromic clubfoot, 605 probands (from 148 multiplex and 457 simplex families) with nonsyndromic clubfoot were evaluated by copy number and oligonucleotide array CGH testing modalities. Only one multiplex family (0.68%) that had 16 with clubfoot and 9 with other foot anomalies, had a 350 kb microduplication, which included the complete duplication of TBX4 and NACA2 and partial duplication of BRIP1. The microduplication was transmitted in an autosomal dominant pattern and all with the microduplication had a range of phenotypes from short wide feet and toes to bilateral clubfoot. Minimal evidence was found for an association between TBX4 and clubfoot and no pathogenic sequence variants were identified in the two known TBX4 hindlimb enhancer elements. Altogether, these results demonstrate that variation in and around the TBX4 gene and the 17q23.1q23.2 microduplication are not a frequent cause of this common orthopedic birth defect and narrows the 17q23.1q23.2 nonsyndromic clubfoot-associated region.
Clubfoot is a common, complex birth defect affecting 4,000 newborns in the United States and 135,000 world-wide each year. The clubfoot deformity is characterized by inward and rigid downward displacement of one or both feet, along with persistent calf muscle hypoplasia. Despite strong evidence for a genetic liability, there is a limited understanding of the genetic and environmental factors contributing to the etiology of clubfoot. The studies described in this dissertation were performed to identify variants and/or genes associated with clubfoot. Genome-wide linkage scan performed on ten multiplex clubfoot families identified seven new chromosomal regions that provide new areas to search for clubfoot genes. Troponin C (TNNC2) the strongest candidate gene, located in 20q12-q13.11, is involved in muscle contraction. Exon sequencing of TNNC2 did not identify any novel coding variants. Interrogation of fifteen muscle contraction genes found strong associations with SNPs located in potential regulatory regions of TPM1 (rs4075583 and rs3805965), TPM2 (rs2025126 and rs2145925) and TNNC2 (rs383112 and rs437122). In previous studies, a strong association was found with rs3801776 located in the basal promoter of HOXA9, a gene also involved in muscle development and patterning. Altogether, this data suggests that SNPs located in potential regulatory regions of genes involved in muscle development and function could alter transcription factor binding leading to changes in gene expression. Functional analysis of 3801776/HOXA9, rs2025126/TPM2 and rs2145925/TPM2 showed altered protein binding, which significantly influenced promoter activity. Although the ancestral allele (G) of rs4075583/TPM1 creates a DNA-protein complex, it did not affect TPM1 promoter activity. However and importantly, in the context of a haplotype, rs4075583/G significantly decreased TPM1 promoter activity. These results suggest dysregulation of multiple skeletal muscle genes, TPM1, TPM2, TNNC2 and HOXA9, working in concert may contribute to clubfoot. However, specific allelic combinations involving these four regulatory SNPs did not confer a significantly higher risk for clubfoot. Other combinations of these variants are being evaluated. Moreover, these variants may interact with yet to be discovered variants in other genes to confer a higher clubfoot risk. Collectively, we show novel evidence for the role of skeletal muscle genes in clubfoot indicating that there are multiple genetic factors contributing to this complex birth defect.