Placental mesenchymal dysplasia and fetal renal-hepatic-pancreatic dysplasia: androgenetic-biparental mosaicism and pathogenesis of an autosomal recessive disorder.

ABSTRACT

Androgenetic-biparental mosaicism (ABM) denotes an embryo in which a subset of cells contains a diploid chromosomal complement derived entirely from the father. Such embryos have a high incidence of placental mesenchymal dysplasia (PMD) and paternal imprinting disorders because the androgenetic cells have pangenomic paternal uniparental disomy. Uniparental disomy also poses a theoretical risk for paternally transmitted autosomal recessive disorders, if both chromosomes of each autosomal pair are identical (isodisomy). We present the 1st example of a recessive disorder, renal-hepatic-pancreatic dysplasia, in a pregnancy complicated by PMD and ABM. Androgenetic-biparental mosaicism was demonstrated in fetal DNA, extracted from multiple organs, by quantitative polymerase chain reaction-based methods that detected allelic imbalances at the differentially methylated SNRPN locus (chromosome 15); polymorphic short tandem repeat microsatellite markers located on chromosomes 4, 7, 8, 13, 18, and 21; and single nucleotide polymorphisms on chromosomes 1 and 19. Laser capture microdissection was performed to isolate specific placental and renal cell populations and document selective enrichment of androgenetic cells in the stroma of PMD and the epithelium of renal cysts. Mutational analysis of coding sequences did not reveal any mutations in NPHP3, a ciliopathy gene implicated in some cases of renal-hepatic-pancreatic dysplasia. Nonetheless, the fetal phenotype and laser capture data support the model of a paternally transmitted autosomal recessive disorder, which occurred because of ABM.