Uniparental Disomy and Disorders of Imprinting

UNIPARENTAL DISOMY IS A FASCINATING and important pathogenetic mechanism, albeit that it is the basis of only a small number of well-defined clinical conditions. At the outset, we may list these seven major syndromes: Prader-Willi syndromeAngelman syndromeBeckwith-Wiedemann syndromeSilver-Russell syndromeTransient neonatal diabetesMaternal uniparental disomy 14 (Temple syndrome)Paternal uniparental disomy 14Prader-Willi syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome can be due to other genetic causes in addition to uniparental disomy (UPD1), and for convenience we include a discussion of these other causes in this chapter. As well as the aforementioned seven conditions, certain other UPDs can be the cause of abnormality. These may manifest, in various combinations, the following traits: intrauterine and postnatal growth retardation, intellectual deficit, congenital malformations, and dysmorphic features. In the small print is first, pseudohypoparathyroidism type 1B, due to upd(20)pat, and second (although this may come to demand a larger-print awareness), the maternal hypomethylation syndrome, which has a particular association with in vitro fertilization (IVF) conceptions (Amor and Halliday, 2008). In a category by itself, UPD can be the cause of homozygosity for an autosomal recessive gene. The foregoing notwithstanding, however, the fact remains that most UPDs appear to be without any phenotypic consequence, and a number of syndromes that had seemed fair candidates turned out not to be due to UPD (Kotzot, 2002).A distinction is to be made between UPD where both chromosomes are identical (uniparental iso-disomy, UPID) and where they are different (uniparental heterodisomy, UPHD) (Fig. 22–1). UPD is normally demonstrable only at the molecular level: typically, although not invariably, the UPD pair of chromosomes are cytogenetically normal, and the karyotype appears normal, 46,XX or 46,XY. The pattern of polymorphic DNA markers shows that both chromosomes have the same haplotype as just one of the chromosomes from one of the parents (isodisomy); or the two chromosomes have the same haplotypes as the chromosome pair from one of the parents (heterodisomy). For example, the chromosome 1 haplotypes from parents and child set out in Figure 22–1b show that the child has two identical copies of one of the father's chromosomes: thus, paternal uniparental isodisomy. This UPD had been discovered fortuitously, when the child was investigated for a clinical diagnosis of congenital insensitivity to pain, an autosomal recessive disorder (Miura et al., 2000). He proved to be homozygous for a mutation in the appropriate gene (TRKA, located at 1q21-q22), and his father carried the mutation, but his mother did not. This scenario—a child with a recessive disorder for which only one parent is heterozygous—is commonly the circumstance behind the discovery of UPIDs that would otherwise have been without clinical effect. The other typical route to recognition of harmless UPDs is an incidental discovery in the course of polymorphic DNA marker analysis being done for other reasons.The state of iso- or heterodisomy can allow an inference as to the site of the initial chromosomal error. Isodisomy typically reflects a meiosis II nondisjunction or a mitotic error, whereas heterodisomy is due to nondisjunction at meiosis I. Partial heterodisomy and partial isodisomy can coexist for the same chromosome pair. For example, a crossover at meiosis I in, say, the distal long arm, followed by meiosis I nondisjunction, could lead to a disomic gamete isodisomic for distal long arm, and heterodisomic for proximal long arm (Fig. 22–1a, lower right). If the nondisjunction were at meiosis II, the isodisomy and heterodisomy would be the other way around, involving the proximal and distal segments, respectively (Fig. 22–1a, lower left).