Gene mapping in syndactyly families

Non-syndromic syndactyly is a common, heterogeneous hereditary condition of webbed fingers and/or toes. It has a prevalence of 3 per 10,000 births. The malformation can be unilateral or bilateral, and the fusion within the web may be cutaneous or bony. Phenotypic variability exists not only between...

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1. Verfasser: Malik, Sajid Perwaiz
Beteiligte: Koch, Manuela C. (Prof. Dr. med.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2005
Humangenetik
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Zusammenfassung:Non-syndromic syndactyly is a common, heterogeneous hereditary condition of webbed fingers and/or toes. It has a prevalence of 3 per 10,000 births. The malformation can be unilateral or bilateral, and the fusion within the web may be cutaneous or bony. Phenotypic variability exists not only between affected individuals, but also within individuals. Nine different types have been described majority of which show autosomal dominant mode of inheritance, except Cenani-Lenz type (type VII) and Malik-Percin syndactyly (type IX) which segregate as autosomal recessive entities. Syndactyly shows failure to achieve a normal limb development, more precisely, the malformation affects the digits number, identity and separation in the last developmental cascades. In this thesis I report on the clinical and molecular data as well as gene localizations in three large Pakistani families with non-syndromic syndactylies. · I have categorized these families according to the existing syndactyly classification. · I have proposed a clinical protocol which helps to use the existing systematics of syndactyly, and on the other hand simplifies the clinical typing of this malformation. · For the first time I report on a family with a novel autosomal recessive hand/foot malformation with mesoaxial synostotic syndactyly (Family 1). In order to classify this type, I have extended the existing syndactyly systematics and have proposed a new name for this novel syndactyly: mesoaxial synostotic syndactyly with phalangeal reduction (MSSD); type IX syndactyly, Malik-Percin type. This term was introduced into the international literature. Through a genome-wide study with highly polymorphic microsatellite markers and linkage analysis, I have localized this unique autosomal recessive syndactyly phenotype on chromosome 17p13.3 with a disease interval of ~5 cM. · By my own experience of phenotyping limb defects in different families and by reviewing the international literature I propose that type I syndactyly has at least four subtypes. I have established that zygodactyly in Family 2, the most common subtype, has a locus on chromosome 3p21.31 with a critical interval of ~0.38 Mb. Additionally, I provide molecular evidence of further genetic heterogeneity within zygodactyly. Considering the high prevalence of zygodactyly in all populations I expect, that diverse loci are responsible for the phenotype and therefore I expect more loci. · Since HOXD13 gene has been excluded in Family 3, therefore, I have good evidence that syndactyly type II is genetically heterogeneous. A genome-wide search has depicted that the phenotype in this family is mapped on chromosome 14q12 and might have a modifier locus on chromosome 2q34-q36. The discovery of three novel loci for syndactylies will significantly help in the clinical and genetic delineation of this complex limb malformation. It will be of tremendous help to the families with limb malformations seeking genetic advice. The ultimate elucidation of the underlying genes might increase our understanding of limb development, especially in the context of getting insight into the developmental cascades of digit number, identity and separation.