The unfolding of the genetic story of Prader-Willi and Angelman syndromes provided the first recognition of human genomic imprinting. These disorders, which are clinically very distinct, are related through their genomic proximity and the inverse direction of the imprinting which affects them. Both are interesting disorders in themselves, especially in that both have distinctive behavioral patterns among their clinical features that may teach us much about normal human behavior.Prader-Willi syndrome (PWS) is a complex multi-system condition whose major features include infantile hypotonia with decreased arousal, poor suck and failure-to-thrive; characteristic dysmorphic facial features; hypopigmentation; childhood onset of obesity due to lack of satiety; hypogonadotropic hypogonadism with genital hypoplasia and delayed and incomplete puberty; short stature for genetic background; developmental delay and usually mild mental retardation; and a characteristic behavioral disturbance with temper tantrums and obsessive-compulsive behavior. PWS occurs in about 1/15,000 people. Since its first description in 1956, it has been apparent that many of these features arise from insufficient function of the hypothalamus, and recent identification of neurosecretory growth hormone insufficiency and temperature and sleep regulation abnormalities support this. However, no visible gross or microscopic abnormalities of the hypothalamus are seen on neuropathology. The finding of a chromosome 15q 11-13 deletion in a proportion of patients with PWS by Ledbetter and colleagues in 1981 was the first window to the exciting genetic discoveries of the past decade, including recognition (initially by Butler and Palmer) that the deletion is always on the paternally-derived chromosome 15 in PWS, and the finding by Nicholls and coworkers that the vast majority of the remainder of patients had normal chromosomes but had maternal uniparental disomy (UPD). Nearly all patients with clinically typical PWS have either 15q deletion (about 75%) or maternal UPD (about 25%). This is the first human disorder that was recognized to result from uniparental disomy, and lead to many insights into imprinting.
Prenatal diagnosis of mosaic ring chromosome 15 with abnormal maternal serum Down syndrome screening and Dandy-Walker malformation
