Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting.

The Prader-Willi syndrome (PWS) critical region on 15q11-q13 is subject to imprinting. PWS becomes apparent when genes on the paternally inherited chromosome are not expressed. Familial PWS is rare. We report on a family in which a male and a female paternal first cousin both have PWS with cytogenetically normal karyotypes. Fluorescence in situ hybridization (FISH) analysis shows a submicroscopic deletion of SNRPN, but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3. The cousins' fathers and two paternal aunts have the same deletion and are clinically normal. The grandmother of the cousins is deceased and not available for study, and their grandfather is not deleted for SNRPN. DNA methylation analysis of D15S63 is consistent with an abnormality of the imprinting center associated with PWS. "Grandmatrilineal" inheritance occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In this case, PWS does not become evident as long as the deletion is passed through the matrilineal line. This represents a unique inheritance pattern due to imprinting.

Ullrich-Turner syndrome in an XY female fetus with deletion of the sex-determining portion of the Y chromosome.

Here we describe a fetus in whom a cystic hygroma was detected by ultrasound during the second trimester. Autopsy demonstrated a female fetus with manifestations of Ullrich-Turner syndrome, including gonadal dysgenesis, generalized lymphedema, and preductal aortic coarctation. Surprisingly, the karyotype was 46,XY, with no evidence of mosaicism for a 45,X cell line. Y-DNA hybridization studies demonstrated a deletion of the sex-determining segment of the short arm of the Y chromosome. This is the first report, in a fetus, of XY Ullrich-Turner syndrome due to a Y chromosome deletion.

XY gonadal dysgenesis: genetic heterogeneity based upon clinical observations, H-Y antigen status and segregation analysis.

Clinical observations and segregation analysis indicate that XY gonadal dysgenesis is characterized by genetic heterogeneity. In addition to the type inherited in X-linked recessive fashion, segregation analysis of other families suggested another type by revealing that the proportion of affected sibs did not differ from that expected on the basis of a male-limited autosomal recessive inheritance. Further heterogeneity may be deduced on the basis of coexisting campomelic dwarfism or possibly also renal parenchymal abnormalities. These observations of genetic heterogeneity must be considered when interpreting studies in which individuals with XY gonadal dysgenesis may or may not show H-Y antigen.