The severe phenotype of human females whose karyotype includes tiny ring X chromosomes has been attributed to the inability of the small ring X chromosome to inactivate. The XIST locus is expressed only from the inactive X chromosome, resides at the putative X inactivation center, and is considered a prime player in the initiation ofmammalian X dosage compensation. Using PCR, Southern blot analysis, and in situ hybridization, we have looked for the presence ofthe XIST locus in tiny ring X chromosomes from eight females who have multiple congenital malformations and severe mental retardation. Our studies reveal heterogeneity within this group; some rings lack the XIST locus, while others have sequences homologous to probes for XIST. However, in the latter, the locus is either not expressed or negligibly expressed, based on reverse trasrlption-PCR analysis. Therefore, what these tiny ring chromosomes have in common is a level ofXIST tanscription comparable to an active X. AsXIST anscription Is an indicator ofX chromosome inactivity, the absence ofXIST transcription strongly suggests that tiny ring X chromosomes in females with severe phenotypes are mutants in the X chromosome inactivation pathway and that the inability of these rings to inactivate is responsible for the severe phenotypes.Although most conceptuses with X chromosomal monosomies are found among spontaneous abortions, some survive fetal life. In fact, most survivors are remarkably healthy individuals whose intelligence is within the normal range (1, 2). Their phenotypes usually include short stature and failure to maintain normal ovarian structure and function. Commonly, but not invariably, they have dysmorphic features such as widely spaced nipples, narrow palate, small mandible, webbed neck, and lymphedema-a constellation of abnormalities referred to as Turner syndrome. Turner syndrome is also associated with karyotypes that include 46 chromosomes with one normal X chromosome and a second X that is structurally abnormal-i.e., having deletions or reduplications of the long arm. Occasionally the abnormal X is one with breaks in both short and long arms that have led to the formation of a ring X chromosome. The relatively benign nature of the anomalies associated with an X monosomy or the presence of a structurally abnormal X is explained by the fact that females normally have only a single active X chromosome (3). The abnormal (genetically deficient) X is usually inactive due to selection favoring cells in which the normal X is active, and therefore the phenotypes of such females are similar to those with a true X monosomy.On the other hand, some females who are mosaic, 45,X/ The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.46,X,r(X), and whose ring X chromosome is tiny (i.e., Fig. 1) are much more severely affected than those with a nonmosaic 45,X karyotype. They have severe mental ret...

Cytogenetic heteromorphisms and restriction fragment length polymorphisms were used to assign the parental origins of 30 de novo non-homologous Robertsonian translocations. The balanced and unbalanced translocations studied included 20 rob(14q21q) four rob(13q14q)four rob(15q21q) one rob(13q15q), and one rob(13q21q). Significantly more maternally (26/30) than paternally (4/30) derived de novo translocations were noted and all rob(14q21q) ascertained through unbalanced probands (20/20) were maternal in origin. Interestingly, 12/13 probands who were trisomic and informative for proximal chromosome 21q loci were homozygous for the markers tested. Segregation (2:1) of the Robertsonian translocation into one daughter cell in meiosis I and subsequent failure of the chromosome 21 chromatids to separate in meiosis II may account for our observation of homozygosity for proximal chromosome 21 loci in the majority of de novo rearrangements tested.

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