To examine the relationship between replication timing and differential gene transcription in tissue-specific and imprinted settings we have studied the replication timing properties of the human Prader-Willi syndrome (PWS) region on human chromosome 15q11-13. Interphase fluorescence in situ hybridization with an overlapping series of cosmid clones was used to map a PWS replication timing domain to a 500-to 650-kb region that includes the SNRPN gene. This PWS domain replicates late in lymphocytes but predominantly early in neuroblasts, with replication asynchrony observed in both tissues, and appears to colocalize with a genetically imprinted transcription domain showing prominent expression in the brain. A 5-to 30-kb deletion in the 5' region of SNRPN results in the loss of late replication control of this domain in lymphocytes when the deleted chromosome is inherited paternally. This potential allele-specific replication timing control region also appears to colocalize with a putative imprinting control region that has been shown previously to abolish the expression of three imprinted transcripts in this same region.

Rett syndrome is a neurodegenerative disorder that occurs exclusively in females. The syndrome is sporadic in most cases with the exception of a few familial cases with an inheritance pattern through maternal lines. These observations raised the possibility that Rett syndrome may be due to an X-linked dominant mutation which is lethal in the male. To evaluate this hypothesis, we have systematically performed high-resolution chromosome analysis on 28 patients with Rett syndrome searching for deletions and/or translocations. In one patient, a de novo balanced translocation was observed with the chromosome constitution of 46,X,t(X;3) (p22.11;q13.31). This finding supports the hypothesis of an X-linked dominant mutation and suggests that the Rett gene might map to distal Xp21 or proximal Xp22.

Cytogenetic analysis of a 15 month old girl evaluated for severe developmental delay and acral skeletal hypoplasia revealed a predominant 46, XX, r(15) karyotype. Prophase banding analysis showed minimal deletion of the ring chromosome (breakpoints pl2 and q26), while silver staining showed it to have an active nucleolus organizing region, multiple abnormal secondary configurations, and decreased satellite association. Although there was no spontaneous instability in the rest of the karyotype, gentian violet-induced chromosome breakage was significantly increased. The rate of spontaneous sister chromatid exchange was not elevated. Cellular mosaicism for chromosome 15 aneuploidy most likely accounts for the patient’s phenotypic abnormalities.