Recent studies have implicated alpha-satellite DNA as an integral part of the centromere, important for the normal segregation of human chromosomes. To explore the relationship between the normal functioning centromere and alpha-satellite DNA, we have studied eight accessory marker chromosomes in which fluorescence in-situ hybridization could detect neither pancentromeric nor chromosome-specific alpha-satellite DNA. These accessory marker chromosomes were present in the majority of or all cells analyzed and appeared mitotically stable, thereby indicating the presence of a functional centromere. FISH analysis with both chromosome-specific libraries and single-copy YACs, together with microsatellite DNA studies, allowed unequivocal identification of both the origin and structure of these chromosomes. All but one of the marker chromosomes were linear mirror image duplications, and they were present along with either two additional normal chromosomes or with one normal and one deleted chromosome. Indirect immunofluorescence analysis revealed that the centromere protein CENP-B was not present on these markers; however, both CENP-C and CENP-E were present at a position defining a 'neo-centromere'. These studies provide insight into a newly defined class of marker chromosomes that lack detectable alpha-satellite DNA. At least for such marker chromosomes, alpha-satellite DNA at levels detectable by FISH appears unnecessary for chromosome segregation or for the association of CENP-C and CENP-E at a functional centromere.

We describe an infant with del(17) (p11.2p12) whose deleted chromosome was inherited from a mosaic mother. The child had manifestations consistent with Smith-Magenis syndrome. The mother appeared to be of normal intelligence and she had minimal findings of Smith-Magenis syndrome. Separation of chromosome 17 homologues in somatic cell hybrids and molecular studies confirmed the cytogenetic diagnoses and the fact that the mother was mosaic. Furthermore, molecular analysis demonstrated novel breakpoints in this family, with the deletion extending into and completely encompassing the markers duplicated in Charcot-Marie-Tooth (CMT) disease. Although this Smith-Magenis syndrome patient is completely deleted for the CMT region, her electrophysiological findings are different from those found in CMT. This is the only reported case of Smith-Magenis syndrome with transmission from a partially affected mosaic mother. Transmission of interstitial deletions from mosaic parents may be more common than thought; therefore, parental chromosomes should be examined when interstitial deletions are identified.

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We report on an infant with preaxial acrofacial dysostosis (Nager syndrome) who was diagnosed prenatally as having an apparently balanced X/autosome translocation [46,X,t(X;9)(p22.1;q32)mat] inherited from a previously diagnosed mosaic translocation carrier mother [46,XX/46,X,t(X;9)(p22.1;q32)]. Replication studies on amniocytes showed the normal X chromosome to be late replicating while the same studies repeated on the infant's lymphocytes showed the translocated X chromosome to be late replicating in most cells. Late replication studies of the mother's lymphocytes demonstrated that the normal X chromosome was late replicating in most cells. The presence of Nager syndrome in this infant may be the result of critical breakpoints and/or position effects on chromosome 9, inducing expression of a gene responsible for the syndrome.

Five families in which an Xp deletion is segregating and two families in which an X chromosome rearrangement including a deletion of the short arm is segregating were ascertained for study. Normal fertility was seen in all families. Members from 5 of the 7 families manifested short stature (height <5th centile), while normal height was present in two families. Studies of both the FMR-1 and the androgen receptor loci using PCR based X-inactivation analysis demonstrated that in all families analyzed, there is preferential inactivation of one X chromosome. Molecular cytogenetic analysis showed that members of 3 of the 7 families share a common breakpoint in an approximate 2-3 Mb region at Xp22.12, suggesting a possible hotspot for chromatin breakage. Previous genotype-phenotype correlations and deletion mapping have indicated that a gene for stature resides within the pseudoautosomal region in Xp22.33. Our findings indicate that the loss of this region is not always associated with short stature, suggesting that other factors may be involved.