Prader Willi/Angelman (SNPRN) LPU005 - Detail

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurogenetic disorders, caused by the loss of function of genes on chromosome 15, bands 15q11-13 on either the paternally or maternally inherited chromosome respectively¹. PWS patients typically exhibit severe neonatal hypotonia, obesity developing in early childhood, hypogonadism, short stature, small hands and feet, mild facial dysmorphism and mild to moderate mental retardation. AS is characterised by microcephaly, jerky movements, absence of speech, abnormal EEG, paroxysms of laughter, and severe mental retardation.

In 70% of patients a large interstitial deletion of 3-4 Mb is observed^{1, 2} and in 2- 4% of patients an imprinting defect is observed of which 25% involve an approx. 200 Kb deletion of the Imprinting Centre (IC) ³. Uniparental disomy, in which the chromosome 15 are inherited from the same parent, accounts for most of the remaining patients with PWS but only 80% of AS patients. The remaining AS patients are believed to have mutations of one or more genes (UBE3A) in the critical region.

The SNRPN gene is one of four imprinted loci that is expressed from the paternal chromosome 15 region 15q11-13 and maps to the smallest deletion region involved in PWS. Its chromosomal location and imprinting status suggest a possible role in the aetiology of PWS⁴.

The imprinting centre (IC) maps to a 100 kb region proximal to SNRPN and includes exon 1 of SNRPN. Parental deletions or mutations in the IC impair the imprinting process in 15q11-13 and cause the two distinct diseases in their offspring^5,6. Most of the PWS imprinting deletions involve SNRPN and are approx. 200 kb. The AS imprinting deletions are small (approx. 40 Kb) and involve the BD3 region however do not include SNRPN.

The Prader-Willi/Angelman Region probe is approximately 150 kb of genomic DNA and targets all the SNRPN gene and all of the imprinting centre. The probe is intended to identify the 3-4 Mb deletions incorporating SNRPN common to 70% of PWS/AS and the smaller deletions of approx. 200 kb incorporating SNRPN and the Imprinting Centre found in PWS. The probe cannot be used to detect smaller deletions or mutations of the Imprinting Centre found in AS or used to detect uniparental disomy. It is designed for fluorescence in situ hybridisation of interphase cells and metaphase chromosomes from fixed cultured peripheral blood cells. The 15qter subtelomere specific probe (clone154P1) allows identification of chromosome 15 and acts as a control probe.

Reference:/Bibliographie/Literatur/Bibliografia

1. Butler, M.G.(1990) Am J Med Genet 35: 319-332
2. Clayton-Smith, J. Pembrey, M. (1992) J Med Genet 29: 412-415
3. Buiting, K. et al (1998) Am J Hum Genet 63 (1): 170-180
4. Glenn, C. et al (1996) Am J Hum Genet 58: 335-346
5. Buiting, K. et al (1995) Nat Genet 9: 395-400
6. Dittrich, B. et al (1996) Nat Genet 14: 163-170