Laboratory Testing for Prader-Willi Syndrome

Abstract

In 1981, Ledbetter and co-workers described a cytogenetically visible deletion in proximal 15q in four patients with Prader-Willi syndrome (PWS). Proximal 15q was targeted for analysis because several previously published Prader-Willi cases exhibited an isochromosome 15q or a translocation with proximal 15q breakpoints. Since the fi rst report of the cytogenetic deletion of proximal 15q in PWS, several cytogenetic and molecular genetic techniques have been used to further characterize the chromosome 15q11–q13 region and for laboratory diagnostic purposes in a range of PWS subjects having a variety of abnormal chromosome fi ndings. Using several chromosome staining methods to evaluate chromosome 15 short arm variants, Butler and Palmer showed that the PWS deletion preferentially involves the paternally inherited chromosome 15. Butler subsequently reported that short arm or C-band variants appeared to be more common in chromosome 15s with a deletion than in normal 15s. Nicholls, Butler, and co-workers studied the parental origin of the chromosome 15 pair in two PWS patients who did not exhibit a 15q deletion. They were the fi rst to describe uniparental disomy (UPD) in PWS and concluded that genetic imprinting in this region must play a causal role in both PWS and Angelman syndrome (AS). One of their PWS patients carried a familial robertsonian 13;15 translocation. What they could not recognize at the time was the causal relationship between robertsonian translocations and UPD. Aside from these important early studies, a large variety of balanced and unbalanced chromosome 15 rearrangements have been described in PWS patients. Most of the chromosome 15 rearrangements associated with PWS have resulted in deletion of proximal 15q, and in many of these cases deletion of the paternally inherited chromosome 15 was demonstrated. Some unusual chromosomal causes of PWS that have been described include intrachromosomal triplication and an unbalanced reciprocal translocation resulting in maternal disomy for proximal 15q. In contrast to the deletion cases, PWS and AS patients who