Synpolydactyly and HOXD13 polyalanine repeat: addition of 2 alanine residues is without clinical consequences
1 Zentrum für Humangenetik, Philipps-Universität Marburg, Bahnhofstr. 7, 35037 Marburg, Germany
2 Department of Biological Sciences, Quaid-I-Azam University, 45320 Islamabad, Pakistan
3 Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014, Uttar Pradesh, India
4 Division of Pediatric Surgery, Department of Surgery, Era's Lucknow Medical College, Hardoi Road, Sarfarazganj, Lucknow-226003, Uttar Pradesh, India
BMC Medical Genetics 2007, 8:78 doi:10.1186/1471-2350-8-78Published: 11 December 2007
Type II syndactyly or synpolydactyly (SPD) is clinically very heterogeneous, and genetically three distinct SPD conditions are known and have been designated as SPD1, SPD2 and SPD3, respectively. SPD1 type is associated with expansion mutations in HOXD13, resulting in an addition of ≥ 7 alanine residues to the polyalanine repeat. It has been suggested that expansions ≤ 6 alanine residues go without medical attention, as no such expansion has ever been reported with the SPD1 phenotype.
We describe a large Pakistani and an Indian family with SPD. We perform detailed clinical and molecular analyses to identify the genetic basis of this malformation.
We have identified four distinct clinical categories for the SPD1 phenotype observed in the affected subjects in both families. Next, we show that a milder foot phenotype, previously described as a separate entity, is in fact a part of the SPD1 phenotypic spectrum. Then, we demonstrate that the phenotype in both families segregates with an identical expansion mutation of 21 bp in HOXD13. Finally, we show that the HOXD13 polyalanine repeat is polymorphic, and the expansion of 2 alanine residues, evident in unaffected subjects of both families, is without clinical consequences.
It is the first molecular evidence supporting the hypothesis that expansion of ≤ 6 alanine residues in the HOXD13 polyalanine repeat is not associated with the SPD1 phenotype.