A KINDRED EXHIBITING COSEGREGATION OF AN OVERLAP CONNECTIVE-TISSUE DISORDER AND THE CHROMOSOME-16 LINKED FORM OF AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE

Autosomal dominant polycystic kidney disease (ADPKD) is a disorder of adult onset manifested by bilaterally enlarged cystic kidneys frequent ly associated with progressive renal failure. The mutated gene (PKD1) responsible for 85 to 95% of cases has been localized to a small segme nt on the distal tip of the short arm of chromosome 16. A clinical spe ctrum of heritable connective tissue disorders that remain unclassifia ble under the present nosology but that contain elements of the Marfan 's syndrome have previously been described. The genetic localization a nd molecular basis of such overlap connective tissue disorders (OCTD) have not been elucidated. In this report, a kindred in which ADPKD and OCTD appear to cosegregate is described. The connective tissue phenot ype in this family includes aortic root dilation, aortic and vertebral artery aneurysms with dissection, and aortic valve incompetence, as w ell as pectus abnormalities, pes planus, joint laxity, arachnodactyly, scoliosis, dolichostenomelia, and high arched palate. ADPKD was manif est primarily as bilateral renal cysts with or without renal failure. The DNA of all living family members was studied with markers recogniz ing polymorphic loci flanking the PKD1 region (3'HVR and 090a), as wel l as markers from the loci of chromosomes 15 and 5, associated with fi brillin genes FBN1 and FBN2, respectively. In this kindred of 20 famil y members traced through five generations, cosegregation of ADPKD and the OCTD phenotype was observed in 12 of 12 meioses and 3 of 3 phase k nown. Both markers for PKD1 were tightly linked to both ADPKD and OCTD , whereas there was no evidence for linkage with either fibrillin locu s. In this family, the ADPKD and OCTD mutations are genetically linked . The presence of OCTD with ADPKD identifies a group of patients at si gnificantly greater risk for sudden death from aortic root and other v ascular aneurysmal dissection and rupture.