Connexion

GENATLAS PHENOTYPE

last update : 19-04-2011

Symbol	PWS
Location	15q11.2-q13
Name	Prader-Willi syndrome
Corresponding gene	SNRPN , SNORD116@ , NDN , MAGEL2 , OCA2
Other symbol(s)	DEL15Q12, UPD15M
Main clinical features	hypotonia and feeding difficulties in early infancy, followed in early childhood by excessive eating and obesity, distinctive facial features, acromicria, short stature, hypogonadism, developmental delay, mild to moderate mental retardation, distinctive behavioral phenotype with temper tantrum and obsessive compulsive mannerisms plasma ghrelin is increased 3- to 4-fold , linked to obesity loss of MAGEL2 contributes to endocrine dysfunction of hypothalamic origin in individuals with PWS (PMID: 21248145))
Genetic determination	chromosomal
	genomic disorder
	epigenetic
Prevalence	~1/22,000 livebirths but with a population prevalence of ~1/54,000
Function/system disorder	multisystem/generalized
	mental retardation
Type	MCA/MR

Gene product

Name

contiguous gene syndrome, including five paternally expressed genes that encode polypeptides : SNURF-SNRPN, MKRN3, MAGEL2, and NDN. SNRPN is a small ribonuclear protein involved in alternative mRNA splicing. No abnormal gene product associated with PWS has been identified

Mechanism(s)

Gene mutation	Chromosome rearrangement	Effect	Comments

	deletion	haploinsufficiency	genomic disorder, typically deleted region between BP1-BP3 (class I), or between BP2-BP3 (class II) on the paternal chromosome
	uniparental disomy	absent protein	maternal UPD, associated with advanced maternal age (trisomy rescue)
imprinting defect		absent protein	microdeletions or LOI at the 3'end of the ICR

Remark(s)

paternal deletions in ~ 65-70 p.cent of cases, maternal UPD in ~ 20-30p.cent, imprinting defect in ~ 5 p.cent

loss of the regulatory psnoRNAs (shorter RNAs psnoRNAs, processed snoRNAs) could be a significant contribution to the etiology of PWS and substitution of the short psnoRNAs could be a therapeutic principle for the disease (PMID: 20053671)); paternally inherited 236kb microdeletion confirms a significant role for the SNORD116 C/D box snoRNA cluster in PWS (PMID: 20588305))

associated with the loss of several species of small nucleolar RNAs (snoRNAs) (PMID: 20876107))

advanced maternal age at childbirth is a predisposing factor for the development of upd(15)mat because of increased M1 errors (PMID: 21633360))

in Prader-Willi Syndrome, loss of MAGEL2 may likewise abolish leptin responses in POMC hypothalamic neurons, which could contribute to the hyperphagia and obesity (PMID: 23341784))

Genotype/Phenotype correlations

UPD patients tend to have a less severe phenotype than deletion patients (facial appearance, hypopigmentation, seizures, mental retardation, behavioral problems)

class I patients tend to have more severe cognitive and behavioral problems than class II patients

atypical larger deletions extending distally have an extended PWS phenotype more severe than classical PWS