Abstract Information

Presenting Author(s) Dominic Furniss
Abstract Title A Screening Panel Of Limb Malformations For Human Genetic Studies
Full author List D. Furniss, S-H Kan, D. Johnson, P. Critchley, H. Giele, AOM Wilkie
Text of abstract

Background: The limb is a classical system for exploring mechanisms of development and morphogenesis. Model organisms commonly utilised include the mouse and chick. Human limb malformations are common, affecting 1 in 500 live births. Despite this, the systematic molecular genetic analysis of human limb malformation is a relatively neglected area.

Methods: We are prospectively collecting DNA from an unselected cohort of patients presenting to the limb malformation clinic at the Department of Plastic and Reconstructive Surgery in Oxford. Currently, the number of patients in the panel is 157. Using denaturing high performance liquid chromatography (DHPLC) followed by DNA sequencing, we have screened for mutations in HOXD13 and GLI3 in this cohort. Functional studies have been performed for selected mutations.

Results: Pathogenic mutations in HOXD13 were demonstrated in 5/128 (3.9%) of patients. A particularly interesting homeodomain mutation, p.I314L, was shown to confer mixed gain and loss of affinity for DNA binding targets. Pathogenic mutations in GLI3 were demonstrated in 4/157 (2.5%) of patients, one of which is instructive in distinguishing the Greig and Pallister-Hall syndrome phenotypes associated with GLI3 mutation.

Conclusion: We have provided the first estimates of the prevalence of mutations in specific genes causing human limb malformations in an unselected clinical cohort. This panel provides a valuable resource for mutation screening of genes identified as playing an important role in limb development in model organisms, as well as for epidemiological studies of the prevalence of mutations causing limb malformations.

Which session is your work most relevant to: Human limb abnormalities