Splitt, Miranda Penman; (1999) Genetic determination of the left-right axis in man: A homozygosity mapping study of heterotaxia in an inbred population. Doctoral thesis (M.D), UCL (University College London).

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Abstract

All vertebrate species show bilateral asymmetry about the midline. Orientation of the heart and viscera is nonrandom or handed and this handed asymmetry is conserved between species. Defects of lateralization include complete situs inversus and heterotaxia in which individual organ situs is discordant. Heterotaxia is almost always associated with complex heart defects. In man the aetiology of most defects of lateralization is unknown but familial cases provide evidence for a genetic component. Study of animal models shows that determination of left right asymmetry is a complex process under the control of many different genes. A series of 68 patients with laterality disturbance ascertained through Paediatric Cardiology Centres is described. The majority of patients had right or left isomerism sequence. There were 43 sporadic cases, 12 familial cases and 13 cases with consanguineous parents. In an attempt to localise a gene for heterotaxia, a homozygosity mapping study was undertaken using 11 patients of Pakistani origin and their consanguineous parents. A whole genome screen with average marker spacing of 14cM was performed. No regions were found to be homozygous by descent (HBD) in all 11 probands. All potential regions of shared HBD in 6 or more affected individuals were excluded by genotyping intervening markers. It is likely that this approach was unsuccessful because heterotaxia is genetically heterogeneous even within this genetically isolated population. Further linkage studies should be confined to single inbred pedigrees. Mutations in the gene for the gap junction protein , connexin 43, have been reported in patients with isomerism sequence. Direct sequencing of the carboxy terminal of connexin 43 in 50 patients did not reveal any changes from the published consensus sequence. The role of this gene in establishing left right asymmetry remains to be proved.

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