Forty-nine individuals have been identified with deletions or translocations involving the short arm of chromosome 5. While most display the classical phenotype of the cri-du-chat syndrome, several of the patients do not have the syndrome or have only a subset of the clinical features. Somatic cell hybrids containing the deleted chromosome 5 were derived from each patient. Each somatic cell hybrid was analyzed at the DNA level using 136 chromosome 5p-specific DNA fragments. It was possible to unambiguously order most of the chromosomal breakpoints present in the somatic cell hybrids based on the hybridization patterns of Southern blots. Further comparisons between the deletions present in the patients and their clinical features identified several chromosomal regions that were involved in specific clinical features. A critical chromosomal region involved the high-pitched cry mapped to 5p15.3, while the chromosomal region involved in the remaining features of the cri-du-chat syndrome mapped to a small region within 5p15.2. Deletions that did not include these two chromosomal regions presented varying clinical phenotypes from severe mental retardation and microcephaly to a clinically normal phenotype. These results demonstrate the need for careful characterization of a 5p deletion in prenatal cases before clinical predictions are made.
Cri-du-chat syndrome is associated with a deletion of the short arm of chromosome 5. Through the phenotypic and molecular analyses of individuals with a subset of the features associated with the syndrome, the genes involved in the syndrome have been mapped to two distinct critical regions. Deletion of a critical region in 5p15.2 results in the distinct facial features associated with the syndrome as well as the severe mental and developmental delay, while a deletion of 5pl 5.3 is associated only with the characteristic cat-like cry, the key diagnostic feature of the syndrome. Therefore, subtle differences in the extent of the 5p deletion can have a profound affect on the prognosis of the patient. In order to more easily differentiate between deletions that lead to the cri-du-chat syndrome phenotype and deletions that lead only to the isolated cat-like cry, we have constructed YAC contigs that span both critical regions. The YAC clones have been used to isolate cosmids mapping to each critical region and cosmids that lie just within the two critical region boundaries have been identified. We report here on the use of these cosmids as probes for fluorescent in situ hybridization experiments on interphase nuclei as a means of more accurately differentiating between small 5p deletions that coincide with a complete cri-du-chat syndrome phenotype and the severe mental and developmental delay that is associated with it and deletions that only delete the distal critical region that coincide with the isolated cat-like cry and a much improved prognosis.
The short arm of human chromosome 5 contains ∼48 Mb of DNA and comprises 1.5% of the genome. We have constructed a mega-YAC/ STS map of this region that includes 436 YACs anchored by 216 STSs. By combining and integrating our map with the 5p maps of other groups using the same recombinant DNA library, a comprehensive map was constructed that includes 552 YACs and 504 markers. The YAC map covers >94% of 5p in four YAC contigs, bridges the centromere, and includes an additional 5 Mb of 5q DNA. The average marker density is 95 kb. This integrated 5p map will serve as a resource for the continuing localization of genes on the short arm of human chromosome 5 and as a framework for both generating and aligning the DNA sequence of this region.One of the primary initial goals of the Human Genome Project was to establish a physical map representing every chromosome of the human genome (Botstein et al. 1990). Advancements toward this end include detailed maps of chromosomes Y (Foote et al. 1992), 3 (Gemmill et al. 1995), 11 (Qin et al. 1996), 12 (Krauter et al. 1995), 16 (Doggett et al. 1995) 19 (Ashworth et al. 1995), 21 (Chumakov et al. 1992Nizetic et al. 1994), 22 (Bell et al. 1995Collins et al. 1995), 7 (Bouffard et al. 1997), and X (Crollius et al. 1996Nagaraja et al. 1997) as well as maps consisting of large segments of the entire genome (Cohen et al.,1993;Chumakov et al. 1995;Hudson et al. 1995Schuler et al. 1996;Deloukas et al. 1998). These contributions will be critical for correctly aligning future DNA sequences (Venter et al. 1998) and the ultimate understanding of human biology and disease (Collins et al. 1998).One of the best studied and more common (1: 50,000 births; Niebuhr 1978) human deletion syndromes is cri-du-chat (Lejuene et al. 1963; Niebuhr 1978). This syndrome results from a deletion of all or part of the short arm of chromosome 5. Previous efforts have yielded YAC contigs Gersh et al. 1997) covering the gene regions considered to account for some of the primary features of this syndrome Church et al. 1995;Gersh et al. 1995). Cri-du-chat breakpoints are known to occur throughout most of the 5p region . A detailed physical map of the entire chromosome arm would provide a valuable resource for future studies. In this paper, we describe an integrated chromosome YAC/STS physical map of 5p, which provides nearly complete coverage of this 48-Mb arm. RESULTS AND DISCUSSION Overview of the ProjectThe integrated 5p YAC/STS map was constructed by a multitiered approach as follows: (1) Nucleation was obtained with 84 regionally ordered 5p STS markers generated from flow-sorted chromosomes for this study ; approximately one STS/0.6 Mb). The Genethon physical map of the human genome (Cohen et al. 1993;Chumakov et al. 1995) was examined to identify tier one to three mega-YACs likely to be derived from 5p. All 84 STSs were used to screen this subset of mega-YAC clones producing YAC contigs spanning 40.8 Mb or ∼85% of the short arm of chromosome 5. (2)
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.