Uniparental Disomy
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P83
2025-12-04
91
Chromosome nondisjunction most commonly results in trisomy or monosomy for the particular chromosome involved in the segregation error. However, less commonly, it can also lead to a disomic state in which both copies of a chromosome derive from the same parent, rather than one copy being inherited from the mother and the other from the father. This situation, called uniparental disomy, is defined as the presence of a disomic cell line containing two chromosomes, or portions thereof, that are inherited from only one parent. If the two chromosomes are derived from identical sister chromatids, the situation is described as isodisomy; if both homologs from one parent are present, the situation is heterodisomy (Fig. 1).
Fig1. Uniparental disomy (UPD), isodisomy, and heterodisomy examples. (A) The formation of UPD. Blue color represents paternal and maroon color represents chromosomes of maternal origin. The nondisjunction could arise in either the maternal or paternal germline. (B) Heterodisomy and isodisomy examples represented. Three offsprings with the following chromosomes are observed: normal biparental inheritance of the example chromosome, maternal heterodisomy with one of each of the mother’s chromosomes, and two potential types of uniparental isodisomy with two copies of either of the mother’s chromosomes (denoted as a and b). (Modified from Preece MA, Moore GE: Genomic imprinting, uniparental disomy and foetal growth, Trends Endocrinol Metabol 11:270–275, 2000.)
The most common explanation for uniparental disomy is trisomy rescue due to chromosome nondisjunction in cells of a trisomic conceptus to restore a disomic state. The cause of the originating trisomy is typical meiotic nondisjunction in one of the parental germlines; the rescue results from a second nondisjunction event, this one occurring mitotically at an early postzygotic stage, thus rescuing a fetus that otherwise would most likely be aborted spontaneously (the most common fate for any trisomic fetus). Depending on the stage and parent of the original nondisjunction event (i.e., maternal or paternal meiosis I or II), the location of meiotic recombination events, and which chromosome is subsequently lost in the postzygotic mitotic nondisjunction event, the resulting fetus or liveborn can have complete or partial isodisomy or heterodisomy for the relevant chromosome.
Although it is not known how common uniparental disomy is overall, it has been documented for most chromosomes in the karyotype by demonstrating uniparental inheritance of polymorphisms in a family. Clinical abnormalities, however, have been demonstrated for only some of these, typically in cases when an imprinted region is present in two copies from one parent (see the section on genomic imprinting later in this chapter) or when a typically recessive condition (which would ordinarily imply that both parents are obligate carriers) is observed in a patient who has only one documented carrier parent. It is important to stress that, although such conditions frequently come to clinical attention because of variants in individual genes or in imprinted regions, the underlying mechanism in cases of uniparental disomy is abnormal chromosome segregation.
Other Disorders Due to Uniparental Disomy
Although it is unclear how common uniparental disomy is, it may provide an explanation for a disease when an imprinted region (see the section on genomic imprinting later in this chapter) is present in two copies from one parent. Thus physicians and genetic counselors must keep imprinting in mind as a possible cause of genetic disorders.
For example, a few patients with cystic fibrosis and short stature have been described with two identical copies of most or the entirety of their maternal chromosome 7. In these cases, the mother happened to be a carrier for cystic fibrosis, and because the child received two maternal copies of the mutant cystic fibrosis gene and no paternal copy of the normal allele at this locus, the child developed the disease. The growth failure was unexplained but might be related to loss of unidentified paternally imprinted genes on chromosome 7.
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