Cholestasis with lymphedema (Aagenaes syndrome): Genome screen and evaluation of candidate regions. L. Bull¹, E. Roche¹, K. Eiklid², C. van der Hagen², A. Knisely³, O. Aagenaes², N. Freimer¹. 1) UCSF, San Francisco, CA; 2) University of Oslo, Oslo, Norway; 3) University of Texas Medical Branch, Galveston, TX.

   Cholestasis with lymphedema (CL), or Aagenaes syndrome, was first described in a Norwegian pedigree, in which the disease demonstrates probable autosomal recessive inheritance. Most Norwegian patients come from the same region, and are descended from a couple born circa 1570. CL is characterized by neonatal-onset cholestatic jaundice, accompanied by elevated levels of serum bile acids, bilirubin, and ALAT, and lasting 1-5 years. Recurrent cholestatic episodes occur in later childhood and adulthood. Lymphedema may be apparent at birth, or begin during childhood, and becomes chronic. Studies on urinary bile acids suggest no inborn bile acid metabolism abnormality. To identify the CL gene, we performed a genome screen using DNA from members of the Norwegian pedigree, and 385 autosomal microsatellite markers. A standard linkage analysis was not feasible because the structure of the pedigree is too complex, and too many samples are unavailable. Therefore, we designed a screening strategy to identify genome regions potentially shared identical by descent among several of these distantly related patients; two sib-pairs and a cousin pair were included. We identified candidate regions based on: 1) data consistent with linkage in the two sib pairs, 2) data consistent with linkage in the cousin pair, 3) evidence for marker haplotypes shared by affected individuals, and 4) evidence that particular marker alleles are more frequent than expected on the disease chromosomes. We paid particular attention to 5 regions containing genes previously found to be mutated in forms of hereditary liver disease or lymphedema (BSEP, FLT4, PGY3, FIC1, and JAG1). We have obtained no genetic evidence that CL is due to mutation in any of these candidate genes. We are currently evaluating 20 candidate regions identified in the genome screen on the basis of the genetic criteria outlined above. These regions are being evaluated by additional genotyping of the samples included in the genome screen, as well as in a larger sample of Norwegian CL patients.