Nonrecurrent Chromosome Abnormalities
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P88-90
2025-12-08
65
Whereas the abnormalities just described are mediated by the landscape of specific genomic features in particular chromosomal regions, many other chromosome abnormalities are due to deletions or rearrangements that have no definitive mechanistic basis. There are many reports of cytogenetically detectable abnormalities in dysmorphic patients involving events such as deletions, duplications, or translocations of one or more chromosomes in the karyotype. Overall, cytogenetically visible autosomal deletions occur with an estimated incidence of 1 in 7000 live births. Most of these have been seen in only a few patients and are not associated with recognized clinical syndromes. Others, however, are sufficiently common to allow delineation of clearly recognizable syndromes in which a series of patients have similar abnormalities.
The defining mechanistic feature of this class of abnormalities is that the underlying chromosomal event is non recurrent; most of them occur de novo and have highly variable breakpoints in the particular chromosomal region, thus distinguishing them as a class from those discussed in the previous section.
Autosomal Deletion Syndromes
One long-recognized syndrome is the cri du chat syndrome, in which there is either a terminal or interstitial deletion of part of the short arm of chromosome 5. This deletion syndrome was given its common name because crying infants with this disorder sound like a meowing cat. The facial appearance (Fig. 1) is distinctive and includes microcephaly, hypertelorism, epicanthal folds, low-set ears, sometimes with preauricular tags, and micrognathia. The overall incidence of the deletion is estimated to be as high as 1 in 15,000 to 50,000 live births.
Fig1. Nonrecurrent deletion syndromes. 4p- deletion syndrome is illustrated by two children supported by 4p-supportgroup. org: (A) Kamila’s smile reveals missing teeth. (B) Sadie shows what some describe as a Greek warrior helmet facial phenotype. (C) Brielle lives with Cri du chat syndrome (fivepminus.org); here, illustrating characteristic hypertelorism, short philtrum, and epicanthal folds. (D) Phenotype-karyotype map of chromosome 5p, based on chromosomal microarray analysis of a series of del(5p) patients. (E) Chromosomal microarray analysis of ~5-Mb deletion in band 1p36.3 (red), which is undetectable by conventional karyotyping. (A, B and C, Photographs by Rick Guidotti, Positive Exposure, www.positiveexposure.org; D, based on data from Zhang X, Snijders A, Segraves R, et al: High-resolution mapping of genotype-phenotype relationships in cri du chat syndrome using array comparative genome hybridization, Am J Hum Genet 76:312–326, 2005; E, courtesy M. Katharine Rudd, Emory Genetics Laboratory, Atlanta, Georgia.)
Most cases of cri du chat syndrome are sporadic; only 10% to 15% of the patients are the offspring of translocation carriers. The breakpoints and extent of the deleted segment of chromosome 5p are highly variable among different individuals, but the critical region missing in all patients with the phenotype has been identified as band 5p15. Many of the clinical findings have been attributed to haploinsufficiency for a gene or genes within specific regions; the degree of intellectual impairment usually correlates with the size of the deletion, although genomic studies suggest that haploinsufficiency for particular regions within 5p14-p15 may contribute disproportionately to severe intellectual disability (see Fig. 1).
Although many large deletions can be appreciated by routine karyotyping, detection of other nonrecurrent deletions requires more detailed analysis by microarrays; this is particularly true for abnormalities involving sub telomeric bands of many chromosomes, which can be difficult to visualize well by routine chromosome banding. For example, one of the most common nonrecurrent abnormalities, the chromosome 1p36 deletion syndrome, has a population incidence of 1 in 5000 and involves a wide range of different breakpoints, all within the terminal 10 Mb of chromosome 1p. Approximately 95% of cases are de novo, and many (e.g., the case illustrated in Fig. 1) are not detectable by routine chromosome analysis.
Typically, and in contrast to the genomic disorders presented in Table 1, the breakpoints are highly variable and reflect a range of different mechanisms, including terminal deletion of the chromosome arm, as seen in 6q deletion (Fig. 2), interstitial deletion of a sub telomeric segment, or recombination between copies of repetitive elements, such as Alu or LINE-1.
Fig2. A deletion at the long-arm terminus of one chromosome 6 as revealed by subtelomeric fluorescence in situ hybridization. Green and red signals reveal intact subtelomeric sequences on the short and long arms of chromosome 6. In this metaphase spread from a patient with congenital abnormalities, we can see the loss of the red signal from one of the chromosome 6 s, consistent with a deletion of materials near the long arm terminus of that chromosome. (Courtesy Charles Lee, The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, United States.)
Table1. Examples of Genomic Disorders Involving Recombination Between Segmental Duplications
Balanced Translocations With Developmental Phenotypes
Reciprocal translocations are relatively common. Most are balanced and involve the precise exchange of chromosomal material between nonhomologous chromosomes; as such, they usually do not have an obvious phenotypic effect. However, among the ~1 in 2000 newborns who have a de novo balanced translocation, the risk for a congenital abnormality is empirically elevated several-fold, leading to the suggestion that some balanced translocations involve direct disruption of a gene or genes by one or both of the translocation breakpoints.
Detailed analysis of a number of such cases by fluorescence in situ hybridization (FISH), microarrays, and targeted or whole genome sequencing has identified defects in protein-coding or noncoding RNA genes in patients with various phenotypes, ranging from developmental delay to congenital heart defects to autism spectrum dis orders. Although the clinical abnormalities in these cases can be ascribed to variants in individual genes located at the site of the translocations, the underlying mechanism in each case is the chromosomal rearrangement itself.
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