Polyalanine Repeat Expansion Mutation Of The HOXD13 Gene In A Chinese Family With Unusual Clinical Manifestations Of Synpolydactyly

Synpolydactyly (SPD) is an autosomal dominant limb malformation caused by mutations in the gene HOXD13. Typically, affected individuals have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web. Urethra disruption occurs in some cases simultaneously. Three genetically distinct SPD loci have been mapped to 2q31, 22q13.31 and 14q11.2–q12, and have been classified into SPD1, SPD2 and SPD3, respectively.The homeobox-containing (HOX) genes encode a family of highly- conserved transcription factors that display important roles in embryonic development. There are four HOX gene clusters (HOXA, HOXB, HOXC and HOXD) located on different chromosomes. HOXD13 is the most 50 member of the HOXD cluster and has two coding exons. Exon 1 contains an imperfect trinucleotide repeat sequence that encodes a 15-residue polymorphic polyalanine tract. Expansion mutations in the polyalanine tract result in SPD1; although expansions of six alanine residues or fewer are though to be non-pathogenic.We investigated a Chinese family in which three individuals across three generations were affected with distinctive limb malformations. All the patients are male, and the inheritance pattern was autosomal dominant. Digital photographs and radiographs were obtained from all affected individuals. Peripheral blood samples were collected from unaffected and affected individuals in this family and another 100 unrelated individuals were used as controls. Primers were designed to amplify exons 1 and 2 of the HOXD13 gene. Chromosome caryotype analysis was carried on for the Proband. Genomic DNA from peripheral leukocytes was extracted from the family members and 100 unrelated individuals using QIAamp DNA Mini Kit. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by the appropriate institutional review committee.The chromosome of the Proband and his father are normal. We used PCR and direct sequencing of amplified PCR products to analyze the HOXD13 genotypes of the three affected and three unaffected individuals in this family, plus 100 unrelated controls. We identified a duplication mutation, c. 186e212dup, in exon 1 of the HOXD13 gene, in all affected individuals in this family. This mutation is predicted to lead to a nine-alanine expansion the polyalanine tract in the N-terminal domain of the HOXD13 protein. It was not present in the unaffected relatives or any of the 100 unrelated controls. All of whom possessed 15 residues in the polyalanine tract. We did not detect any evidence for polymorphism or non-pathogenic expansions in our sample of 100 controls.This Chinese family showed variable clinical features and severity, from minor to more severe manifestations and it is useful to clinicians further understand SPDaccording to newaspects. The three patients characterized by typical SPD phenotypes fulfilling the Temtamy McKusick criteria, minor variants involved with SPD and someunusual featureswhich have never been described thus far. Camptodactyly and symphalangism of fingers two to five involving MP, transverse phalanx and osseous fusion of the third metacarpal and proximal phalanx have added to the list of possible phenotypes caused by HOXD13 polyalanine expansion mutations. In accordance with other studies, we found evidence that identical genotypes could be associated with a variety of phenotypes, which demonstrate the anticipation across generations. Further studies are needed to explore the mechanisms of this anticipation and to explain the marked phenotypic heterogeneity.