HOXD13 polyalanine tract expansion in classical synpolydactyly type Vordingborg

Area of Science:

• Genetics
• Orthopedics
• Human Evolution

Background:

• Autosomal dominant axial synpolydactyly (SPD), also known as the Vordingborg type, was first described in a seven-generation family in 1927.
• Expansion of a polyalanine tract in the HOXD13 gene is the established genetic cause of SPD.
• Understanding the genetic basis and phenotypic variability of SPD is crucial for diagnosis and management.

Purpose of the Study:

• To re-examine the family initially described by Oluf Thomsen with autosomal dominant axial synpolydactyly.
• To identify the specific genetic mutation responsible for SPD in this family.
• To characterize the phenotypic spectrum associated with the identified HOXD13 mutation.

Main Methods:

• Pedigree analysis and clinical examination of affected individuals.
• DNA sequencing to identify mutations in the HOXD13 gene.
• Dermatoglyphic analysis to detect genetic status in cases with inapparent bone malformations.

Main Results:

• The study successfully re-identified members of Thomsen's original family.
• A 9-triplet polyalanine expansion in the HOXD13 gene was detected and confirmed to segregate with the SPD disorder.
• Phenotypic manifestations varied significantly, including severe bone malformations and, in some cases, inapparent skeletal abnormalities detectable only through dermatoglyphics.

Conclusions:

• The 9-triplet polyalanine expansion in HOXD13 is the causative mutation for axial synpolydactyly in the studied family.
• The phenotypic spectrum of HOXD13-associated SPD is broader than previously recognized, encompassing subclinical presentations.
• Dermatoglyphics can serve as a valuable diagnostic tool for identifying genetic carriers of SPD with minimal or no overt bone malformations.