Somatic segregation errors predominantly contribute to the gain or loss of a paternal chromosome leading to uniparental disomy for chromosome 15

• Published in: Clinical genetics Vol. 57; no. 5; pp. 349 - 358
• Main Authors: Robinson, Wendy P., Christian, Susan L., Kuchinka, Brian D., Peñaherrera, Maria S., Das, Soma, Schuffenhauer, Simone, Malcolm, Susan, Schinzel, Albert A., Hassold, Terry J., Ledbetter, David H.
• Format: Journal Article
• Language: English
• Published: Copenhagen Munksgaard International Publishers 01.05.2000; Blackwell
• Subjects: Adult; Aneuploidy; Angelman syndrome; Angelman Syndrome - genetics; Biological and medical sciences; Chromosome aberrations; Chromosome Segregation - genetics; Chromosomes, Human, Pair 15 - genetics; DNA - analysis; Female; Gene Silencing; Humans; In Situ Hybridization, Fluorescence; Infant, Newborn; Male; Maternal Age; Medical genetics; Medical sciences; meiosis; Microsatellite Repeats; mosaicism; Mosaicism - genetics; non-disjunction; Paternal Age; Polymorphism, Restriction Fragment Length; Prader-Willi syndrome; uniparental disomy; X Chromosome - genetics; X-chromosome inactivation; Zygote; Chromosomal aberration; Endocrinopathy; Human; Nervous system diseases; Paternal age; Pathogenesis; Segregation; Diseases of the osteoarticular system; Somatic cell; Happy puppet syndrome; Congenital disease; Genetic determinism; Cerebral disorder; Genetic disease; Maternal age; Uniparental disomy; Malformation; Chromosome D15; Central nervous system disease; Risk factor; Parental origin; Complex syndrome; Prader Labhart Willi syndrome
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1034/j.1399-0004.2000.570505.x

Paternal uniparental disomy (UPD) for chromosome 15 (UPD15), which is found in ∼2% of Angelman syndrome (AS) patients, is much less frequent than maternal UPD15, which is found in 25% of Prader–Willi syndrome patients. Such a difference cannot be easily accounted for if ‘gamete complementation’ is the main mechanism leading to UPD. If we assume that non‐disjunction of chromosome 15 in male meiosis is relatively rare, then the gain or loss of the paternal chromosome involved in paternal and maternal UPD15, respectively, may be more likely to result from a post‐zygotic rather than a meiotic event. To test this hypothesis, the origin of the extra chromosome 15 was determined in 21 AS patients with paternal UPD15 with a paternal origin of the trisomy. Only 4 of 21 paternal UPD15 cases could be clearly attributed to a meiotic error. Furthermore, significant non‐random X‐chromosome inactivation (XCI) observed in maternal UPD15 patients (p<0.001) provides indirect evidence that a post‐zygotic error is also typically involved in loss of the paternal chromosome. The mean maternal and paternal ages of 33.4 and 39.4 years, respectively, for paternal UPD15 cases are increased as compared with normal controls. This may be simply the consequence of an age association with maternal non‐disjunction leading to nullisomy for chromosome 15 in the oocyte, although the higher paternal age in paternal UPD15 as compared with maternal UPD15 cases is suggestive that paternal age may also play a role in the origin of paternal UPD15.