Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (MIM 208085) is an autosomal recessive multisystem disorder that may be associated with germline VPS33B mutations. VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients. We characterised clinical and molecular features of ARC syndrome in order to identify potential genotype-phenotype correlations. The clinical phenotype of 62 ARC syndrome patients was analysed. In addition to classical features described previously, all patients had severe failure to thrive, which was not adequately explained by the degree of liver disease and 10% had structural cardiac defects. Almost half of the patients who underwent diagnostic organ biopsy (7/16) developed life-threatening haemorrhage. We found that most patients (9/11) who suffered severe haemorrhage (7 post biopsy and 4 spontaneous) had normal platelet count and morphology. Germline VPS33B mutations were detected in 28/35 families (48/62 individuals) with ARC syndrome. Several mutations were restricted to specific ethnic groups. Thus p.Arg438X mutation was common in the UK Pakistani families and haplotyping was consistent with a founder mutation with the most recent common ancestor 900-11,000 years ago. Heterozygosity was found in the VPS33B locus in some cases of ARC providing the first evidence of a possible second ARC syndrome gene. In conclusion we state that molecular diagnosis is possible for most children in whom ARC syndrome is suspected and VPS33B mutation analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome.
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