Autosomal dominant polycystic kidney disease (
ADPKD) is a disorder of adult onset manifested by bilaterally enlarged
cystic kidneys frequently associated with progressive
renal failure. The mutated gene (PKD1) responsible for 85 to 95% of cases has been localized to a small segment on the distal tip of the short arm of chromosome 16. A clinical spectrum of heritable connective tissue disorders that remain unclassifiable under the present nosology but that contain elements of the
Marfan's syndrome have previously been described. The genetic localization and 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 phenotype in this family includes aortic root dilation, aortic and vertebral artery
aneurysms with dissection, and
aortic valve incompetence, as well as pectus abnormalities,
pes planus,
joint laxity,
arachnodactyly,
scoliosis, dolichostenomelia, and high arched palate.
ADPKD was manifest primarily as bilateral renal
cysts with or without
renal failure. The
DNA of all living family members was studied with markers recognizing polymorphic loci flanking the PKD1 region (3'HVR and O90a), as well as markers from the loci of chromosomes 15 and 5, associated with
fibrillin genes FBN1 and FBN2, respectively. In this kindred of 20 family members traced through five generations, cosegregation of
ADPKD and the
OCTD phenotype was observed in 12 of 12 meioses and 3 of 3 phase known. Both markers for PKD1 were tightly linked to both
ADPKD and
OCTD, whereas there was no evidence for linkage with either
fibrillin locus. In this family, the
ADPKD and
OCTD mutations are genetically linked. The presence of
OCTD with
ADPKD identifies a group of patients at significantly greater risk for
sudden death from aortic root and other vascular aneurysmal dissection and
rupture.