Complex and segmental uniparental disomy (UPD): review and lessons from rare chromosomal complements

Abstract

Objective-To review all cases with segmental and/or complex uniparental disomy (UPD), to study aetiology and mechanisms of formation, and to draw conclusions. Design-Searching published reports in Medline.Results-The survey found at least nine cases with segmental UPD and a normal karyotype, 22 cases with UPD of a whole chromosome and a simple or a nonhomologous Robertsonian translocation, eight cases with UPD and two isochromosomes, one of the short arm and one of the long arm of a non-acrocentric chromosome, 39 cases with UPD and an isochromosome of the long arm of two homologous acrocentric chromosomes, one case of UPD and an isochromosome 8 associated with a homozygous del(8)(p23.3pter), and 21 cases with UPD of a whole or parts of a chromosome associated with a complex karyotype. Segmental UPD is formed by somatic recombination (isodisomy) or by trisomy rescue. In the latter mechanism, a meiosis I error is associated with meiotic recombination and an additional somatic exchange between two non-uniparental chromatids. Subsequently, the chromatid that originated from the disomic gamete is lost (iso-and heterodisomy). In cases of UPD associated with one isochromosome of the short arm and one isochromosome of the long arm of a non-acrocentric chromosome and in cases of UPD associated with a true isochromosome of an acrocentric chromosome, mitotic complementation is assumed. This term describes the formation by misdivision at the centromere during an early mitosis of a monosomic zygote. In cases of UPD associated with an additional marker chromosome, either mitotic formation of the marker chromosome in a trisomic zygote or fertilisation of a gamete with a marker chromosome formed in meiosis by a disomic gamete or by a normal gamete and subsequent duplication are possible. Conclusions-Research in the field of segmental and/or complex UPD may help to explain undiagnosed non-Mendelian disorders, to recognise hotspots for meiotic and mitotic recombinations, and to show that chromosomal segregation is more complex than previously thought. It may also be helpful to map autosomal recessively inherited genes, genes/regions of genomic imprinting, and dysmorphic phenotypes. Last but not least it would improve genetic counselling. (J Med Genet 2001;38:497-507)

Low incidence of UPD in spontaneous abortions beyond the 5th gestational week

“…34 In conclusion, the incidence of UPD in a series of consecutive spontaneous abortions with normal karyotpes is very low (2.8%). However, the impact of UPD on defects in embryonic development may still be higher than concluded from the present study since increasing numbers of segmental UPDs have recently been reported possibly occurring in highly recombinant regions or instable areas of chromosomal attachment during meiosis (for review see 35 ). Such cases would be likely to escape our holochromosomal UPD approach.…”

Identification of Key Regions and Genes Important in the Pathogenesis of Sézary Syndrome by Combining Genomic and Expression Microarrays

“…2). However, we observed that some individuals, displaying LOH, do not exhibit copy number changes, a condition that might be explained with copy-neutral LOH events also known as UPD (23). The highest incidence, with six samples displaying UPD events, was detected for chromosome 10, whereas not more than two cases have been detected for other chromosomes such as 17 and 9 (boxed areas in Fig.…”

“…In cancer biology, it might unveil genes that are downregulated through epigenetic mechanisms or mutations, but still retain a diploid copy number (32). Events of UPD might be due to: (a) mitotic nondisjunction, leading to UPD of a whole chromosome, (b) recombination between chromatids, resulting in UPD of a chromosomal arm or telomeric ends, (c) multiple recombination events, determining interstitial regions of UPD (9,23). In the SS cases analyzed, we could find several small and few large UPDs involving interstitial or telomeric regions of LOH occurring mainly for chromosome 10 and to a lesser extent for chromosome 9 and 17.…”

Angelman syndrome (AS, MIM 105830)

“…29 Mechanisms of UPD formation are trisomy rescue, gamete complementation, mitotic duplication and post-fertilization errors. 30 The mechanism of paternal UPD of chromosome 15 was described by Robinson et al, 31 showing a somatic segregation error in about 75% of these paternal UPD15 cases. A milder clinical phenotype in patients with paternal UPD has been suggested compared with AS patients with a deletion.…”