Molecular and cytogenetic studies of an X;autosome translocation in a patient with premature ovarian failure and review of the literature.

We have identified a patient with premature ovarian failure (POF) and a balanced X;autosome translocation: 46,X,t(X;6)(q13.3 or q21;p12) using high-resolution cytogenetic analysis and FISH. BrdU analysis showed that her normal X was late-replicating and translocated X earlier-replicating which is typical of balanced X;autosome rearrangements. Molecular studies were done to characterize the breakpoint on Xq and to determine the parental origin. PCR probes of tetranucleotide and dinucleotide repeat polymorphisms, and genomic probes were used to study DNA from the patient, her chromosomally normal parents and brother, and somatic cell hybrids containing each translocation chromosome. The translocation is paternally derived and is localized to Xq13.3-proximal Xq21.1, between PGK1 and DXS447 loci, a distance of 0.1 centimorgans. A "critical region" for normal ovarian function has been proposed for Xq13-q26 [Sarto et al., Am J Hum Genet 25:262-270, 1973; Phelan et al., Am J Obstet Gynecol 129:607-613, 1977; Summitt et al., BD:OAS XIV(6C):219-247, 1978] based on cytogenetic and clinical studies of patients with X;autosome translocations. Few cases have had molecular characterization of the breakpoints to further define the region. While translocations in the region may lead to ovarian dysfunction by disrupting normal meiosis or by a position effect, two recent reports of patients with premature ovarian failure and Xq deletions suggest that there is a gene (POF1) localized to Xq21.3-q27 [Krauss et al., N Engl J Med 317:125-131, 1987; Davies et al., Cytogenet Cell Genet 58:853-966, 1991] or within Xq26.1-q27 [Tharapel et al., Am J Hum Genet 52:463-471, 1993] responsible for POF.(ABSTRACT TRUNCATED AT 250 WORDS)