Uniparental Disomy

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 (see Table 6-1). If the two chromosomes are derived from identical sister chromatids, the situation is described as isodisomy; if both homologues from one parent are present, the situation is heterodisomy.

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; see Table 5-2). 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; see Chapter 7) 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 mutations in individual genes or in imprinted regions, the underlying pathogenomic mechanism in cases of uniparental disomy is abnormal chromosome segregation.