Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology.

Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common hereditary renal cystic diseases and has a high infant mortality. Prenatal diagnosis using fetal sonography can be unreliable, especially in early pregnancy. The ARPKD locus has been mapped to proximal chromosome 6p allowing haplotype-based prenatal diagnosis in "at-risk" families. From December 1994 to March 1997, we received 258 inquiries regarding prenatal evaluation and we have completed analyses in 212 families. To date, 65 prenatal analyses have been performed in 57 families. In the majority of the requesting families (45/57), the index children are deceased and their DNA was extracted from paraffin-embedded tissue. Eighteen fetuses were homozygous for the disease-associated haplotypes. In 12 of these fetuses, pathoanatomical examination demonstrated typical ARPKD changes consisting of dilated collecting ducts and the characteristic hepatic ductal plate malformation. These changes were detected in two fetuses as early as 13 weeks gestational age. These cases represent the earliest demonstration of ARPKD-associated histopathology reported to date. One high risk fetus was carried to term and turned out to be unaffected. However, the diagnosis of ARPKD remained doubtful in the index patient. Forty-three fetuses were either heterozygous or homozygous for a nondisease-associated haplotype and all infants born were phenotypically unaffected at birth. In four cases, a recombination event occurred between the flanking markers and no genotypic prediction was possible. Three of these pregnancies were terminated and necropsy of the fetuses confirmed ARPKD, while one fetus was carried to term and showed no abnormalities at birth. These results show that haplotype-based prenatal testing is feasible and reliable in pregnancies "at risk" for ARPKD. An absolute prerequisite for these studies is an accurate diagnosis of ARPKD in previously affected sib(s).

An integrated genetic and physical map of the autosomal recessive polycystic kidney disease region.

Autosomal recessive polycystic kidney disease is one of the most common hereditary renal cystic diseases in children. Genetic studies have recently assigned the only known locus for this disorder, PKHD1, to chromosome 6p21-p12. We have generated a YAC contig that spans approximately 5 cM of this region, defined by the markers D6S1253-D6S295, and have mapped 43 sequence-tagged sites (STS) within this interval. This set includes 20 novel STSs, which define 12 unique positions in the region, and three ESTs. A minimal set of two YACs spans the segment D6S465-D6S466, which contains PKHD1, and estimates of their sizes based on information in public databases suggest that the size of the critical region is < 3.1 Mb. Twenty-eight STSs map to this interval, giving an average STS density of < 1/150 kb. These resources will be useful for establishing a complete transcription map of the PKHD1 region.

Dominantly transmitted glomerulocystic kidney disease: a distinct genetic entity.

Glomerulocystic kidney disease (GCKD) is a relatively rare condition with both a sporadic and familial occurrence. Pathologically, GCKD is characterized by cystic dilatation of Bowman's space and the initial proximal convoluted tubule. As a heritable disorder, GCKD has primarily been recognized in infants with a family history of classic, autosomal dominant polycystic kidney disease (ADPKD). Dominantly transmitted GCKD associated with either hypoplastic or normal-sized kidneys has also been reported in older children and adults. A large, three-generation African-American family with familial GCKD is characterized. Of the 20 individuals available for study, seven affected individuals were identified by renal sonogram or renal histopathology. GCKD in this family segregates as an autosomal dominant trait as evidenced by its apparent transmission from a father to his sons. A set of directed linkage strategies indicates that the distinctive GCKD phenotype in this family results from a dominantly acting mutation that disrupts a genetic locus distinct from the ADPKD loci, PKD1 and PKD2, as well the human homologue of mouse jcpk mutation, a newly described murine GCKD. These analyses are the first known genetic studies conducted in a family with heritable GCKD and post-infantile age of onset.