X-chromosome inactivation patterns in females with Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by loss of paternally expressed genes from the 15q11-q13 region generally due to a paternally-derived deletion of the 15q11-q13 region or maternal disomy 15 (UPD). Maternal disomy 15 is usually caused by maternal meiosis I non-disjunction associated with advanced maternal age and after fertilization with a normal sperm leading to trisomy 15, a lethal condition unless trisomy rescue occurs with loss of the paternal chromosome 15. To further characterize the pathogenesis of maternal disomy 15 process in PWS, the status of X-chromosome inactivation was calculated to determine whether non-random skewing of X-inactivation is present indicating a small pool of early embryonic cells. We studied X-chromosome inactivation in 25 females with PWS-UPD, 35 with PWS-deletion, and 50 controls (with similar means, medians, and age ranges) using the polymorphic androgen receptor (AR) gene assay. A significant positive correlation (r = 0.5, P = 0.01) was seen between X-chromosome inactivation and age for only the UPD group. Furthermore, a significantly increased level (P = 0.02) of extreme X-inactivation skewness (>90%) was detected in our PWS-UPD group (24%) compared to controls (4%). This observation could indicate that trisomy 15 occurred at conceptus with trisomy rescue in early pregnancy leading to extreme skewness in several PWS-UPD subjects. Extreme X-inactivation skewness may also lead to additional risks for X-linked recessive disorders in PWS females with UPD and extreme X-chromosome skewness.
Butler
Merlin G
MG
Section of Medical Genetics and Molecular Medicine, Children's Mercy Hospitals and Clinics and University of Missouri, Kansas City School of Medicine, Kansas City, Missouri 64108, USA. mgbutler@cmh.edu
Theodoro
Mariana F
MF
Bittel
Douglas C
DC
Kuipers
Paul J
PJ
Driscoll
Daniel J
DJ
Talebizadeh
Zohreh
Z
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D011218:Prader-Willi Syndrome / Q000235:genetics*; D049951:X Chromosome Inactivation