Research article

Synpolydactyly and HOXD13 polyalanine repeat: addition of 2 alanine residues is without clinical consequences

Sajid Malik^1,2 , KM Girisha³ , Muhammad Wajid² , Akhilesh K Roy⁴ , Shubha R Phadke³ , Sayedul Haque² , Wasim Ahmad² , Manuela C Koch¹ and Karl-Heinz Grzeschik¹

¹Zentrum für Humangenetik, Philipps-Universität Marburg, Bahnhofstr. 7, 35037 Marburg, Germany

²Department of Biological Sciences, Quaid-I-Azam University, 45320 Islamabad, Pakistan

³Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014, Uttar Pradesh, India

⁴Division of Pediatric Surgery, Department of Surgery, Era's Lucknow Medical College, Hardoi Road, Sarfarazganj, Lucknow-226003, Uttar Pradesh, India

author email corresponding author email

BMC Medical Genetics 2007, 8:78doi:10.1186/1471-2350-8-78

Published:	11 December 2007

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.