A novel mutation of HOXA13 in a family with hand-foot-genital syndrome and the role of polyalanine expansions in the spectrum of müllerian fusion anomalies

Abstract

OBJECTIVE: Hand-foot-genital syndrome (HFGS) is a rare congenital disease characterized by genitourinary defects, uterovaginal septa, malformation of the distal limbs, and mutations of HOXA13. The severity of HFGS has been shown to be proportional to the length of polyalanine insertions, so other uterovaginal anomalies could potentially fall into this spectrum, perhaps harboring small polyalanine expansions. The purpose of this study is to characterize the genetic basis of true HFGS versus that of isolated, non-HFGS-related uterovaginal septa. Additionally, we report a novel mutation found in a family with HFGS. DESIGN: Case-control study. MATERIALS AND METHODS: Genomic DNA was extracted from biopsies of septa (non-HFGS patients) or blood samples (HFGS family). The entire HOXA13 gene was amplified in seven overlapping sections using PCR, and the products were submitted for DNA sequence analysis. To check for heterozygosity and to allow sequence analysis of each allele separately, PCR products were further cloned into plasmid vectors using TA cloning. RESULTS: A screen of subjects with idiopathic, non-HFGS-related uterine (n=12) or uterovaginal (n=5) septa showed no mutations of HOXA13. Affected members (n=3) of a family with clinically confirmed HFGS were heterozygous for a novel mutation of HOXA13. The mutation is a 30-nucleotide insertion beginning at base 269 that expands the third polyalanine tract by 10 alanine residues. An unaffected family member did not show any HOXA13 mutations. CONCLUSIONS: Without the characteristic hand and foot symptoms, idiopathic septa appear to have a genetic basis that differs from that of true HFGS. An isolated uterovaginal septum seems to be a distinct condition rather than a mild form of HFGS. When patients present with septa, it is not necessary to subject them to x-rays of the distal limbs or to sequence analysis of HOXA13 unless they show clear signs of the other sequelae characteristic of true HFGS.