ABSTRACTS: Oral Presentation Abstracts
Introduction: ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterised by neurogenic Arthrogryposis multiplex congenita, Renal tubular dysfunction and Neonatal Cholestasis with biliary duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common and affected infants fail to thrive and usually die in the first year of life. There are few indications to the aetiology of this disorder and autosomal recessive pattern of inheritance allows use of the Autozygosity Mapping as a tool to search for the genes responsible for this disease.
Methods: We ascertained 11 kindreds containing 25 affected individuals with ARC syndrome. Initially we excluded linkage to the potential candidate genes, ABCB4 and ATP8B1, which are implicated in other disorders that cause neonatal cholestasis with low gGT activity. We then undertook a genome-wide linkage scan using the Affymetryx 10K SNP chip in 7 affected individuals from 6 consanguineous ARC kindreds.
Results: Inspection of the results from the 10,000 SNPs revealed 8 regions of extended homozygosity shared by all affected individuals. These were further analysed by typing microsatellite markers in 64 individuals from 11 consanguineous families. A 3 Megabase region of homozygosity (maximum two-point LOD score of 9.8) within 15q25-q26 was identified.
Conclusion: We have mapped the ARC syndrome locus and mutation analysis of candidate genes by direct sequencing is in progress. Identification of the ARC syndrome gene will offer families a possibility for prenatal diagnosis and novel insights into the pathophysiology of this complex disease.