Genotype Phenotype Correlation In Prader Willi Syndrome

Cristina Skrypnyk- MD, PhD University of Oradea, Romania Faculty of Medicine and Pharmacy, Genetics Department

a contiguous gene syndrome caused by the loss of function of genes situated within the

15q11-q13 region

the molecular events underlying the disorder

- interstitial deletions (70%)

- uniparental disomy (UPD) (25%) - imprinting center defects (<5%) - chromosomal translocations (<1%) - a balanced chr. rear.breaking within

15q11.2-q13 (<1%)

Genotype-phenotype correlation in PWS

Diagnosis of PWS:

Clinical observations

DNA methylation studies (absence of a paternal methylation pattern within 15q11) (FISH) fluorescence in situ hybridization analysis (deletion or nondeletion)

The main limitations:- can not determine the size of the molecular deletions- can not detect microdeletions in the PWS imprinting center

Real-time PCR assay using genomic DNA determine the size of the chromosomal deletions in patients with PWS


Genes have been mapped within the PWS/AS region

SNRPN (small nuclear ribonucleoprotein N), the best-described gene that is likely to cause some features of PWS

Based on studies in the mouse and human, gene expression is from the paternally inherited chromosome 15 only and is primarily in brain and heart


Genes have been mapped within the PWS region

GABRB3, GABRA5, and GABRG3 all GABA-receptor subunit genes

Genes have been mapped within the PWS/AS region

NECDIN (NDN) gene which encodes a DNA-binding protein (necdin) mediates intracellular processes essential for neurite outgrowth, is an antiapoptotic or survival factor in the early development of the nervous system

loss of necdin impinges on axonal outgrowth Necdin gene- reduced sympathetic function provides a plausible

explanation for deficiencies of salivary gland function Lee et all 2005, Andrieu et al 2006

Tnnesse AA et all Dev Dyn. 2008 Jul;237(7):1935-43.


MAGEL2 and MKRN3 are genes in proximity to the NDN locus; transcribed only by the paternal allele and expressed predominantly in the brain.

shown the role in circadian rhythm and have demonstrated several findings that are associated with PWS: neonatal growth retardation, excessive weight gain due to hyperphagia, and increased adiposity with altered metabolism in adulthood

O Neil al 2005, Bischof et al 2007, Koylov et al 2007


P (OCA2) gene, which codes for tyrosinase-positive albinism; its deletion is associated with the hypopigmentation seen in one-third of individuals with PWS

NIPA1, NIPA2, CYFIP1, and GCP5 genes are considered responsible by the obsesive behaviour and a low IQ in patients with big deletions (3 Mb)

Bittel et al. 2006

Distinct differences have been reported between individuals with Prader-Willi syndrome resulting from deletion compared with uniparental maternal disomy 15 in physical, cognitive, and behavioral parameters



individuals with 15q deletion showed a lower birth weight at term, higher frequency of need for special feeding techniques, sleep disturbance, hypopigmentation, speech articulation defects, hypogonadism and a low IQ

Lin et al 2007, Torrado et al 2007

patients with deletions with breakpoint 1 (breaking more proximally) were reported to have more behavior problems than those with deletions with breakpoint 2

their behavior problems included poorer reading and math skills, poorer adaptive behavior skills and specific obsessive-compulsive behaviors and physical depression

Hartley et al 2005

Genotype-phenotype correlation in PWS individuals with UPD are less likely to have the typical facial

appearance, hypopigmentation, or skill with jigsaw puzzles; they also have a somewhat higher IQ and milder behavior problems

Dykens et al 2002, Hartley et al 2005

Some data confirm an increased maternal age in UPD group Lin et al 2007


Psychosis

the affective psychosis and autism spectrum disorders associated with PWS has been found to be mainly confined to UPD(15)mat (62%) rather than to those with a deletion (16%)

psychosis may be related to the presence of two copies rather than a single copy of a gene or genes located in the distal half of the region which is paternally imprinted, but maternally active

thus all of the people with psychosis had two active copies of any imprinted genes in the region while all non-psychotic people (including controls) had only one

Milner et al 2005, Verhoeven et al.2006, Sony et al 2007 Dimitropolous et al 2007

Webb T et all. Am J Med Genet A. 2008 Apr 1;146(7):843-53.


Excessive sleepiness and sleep disordered breathing (SDB)

polysomnograms (PSGs) and multiple sleep latency tests (MSLTs) performed in a cohort of PWS patients in relationship with BMI scores, daytime sleepiness, growth hormone (GH) treatments.

Despite the positive correlation between the body-mass index and apnea-hypopnea index, the type and severity of sleep disordered breathing were not predictable based on underlying genetic defect.

Williams et all. J Clin Sleep Med. 2008 Apr 15;4(2):111-8.


GH therapy results

3-year retrospective study on 46 PWS patients indicates that benefit from GH therapy (0.1 IU/kg/day subcutaneously) in height increase and improved body composition

there is no significant gender or genotype pattern differences among the height, weight, body mass index before and after GH treatment.

Lin HY et al J Chin Med Assoc. 2008 Jun;71(6):305-9.


Scoliosis

a retrospective longitudinal, clinical, and radiologic study performed on 145 patients with confirmed PWS (1980-2006), 64% received growth-hormone therapy

43.4% patients were afflicted with scoliosis scoliosis frequency steadily rose with age, and a large majority of

patients were affected at skeletal maturity (66.7%) scoliosis prevalence was not affected by the genotype or by

growth-hormone treatment. patients with higher BMI values had an increased risk of

developing a kyphotic deformity in association with scoliosis

Odent et all Pediatrics. 2008 Aug;122(2):e499-503


Central adrenal insufficiency

The high percentage (60%) of central adrenal insufficiency in PWS patients might explain, in the recent past, the high rate of sudden death, particularly during infection-related stress.

There was no significant difference reported in age, gender, genotype, and body mass index score between patients with central adrenal insufficiency and those without.

Dudley O et al. J Intellect Disabil Res. 2008 May;52(Pt 5):426-36


Understanding the influence of gene expression on the particular phenotype of PWS, espeacelly on behavioral and cognitive characteristics is in the early stage of research development.

Additional research is needed to identify the function of these genes and their interaction with gene networks to clarify the potential role they play.

It is important to confirm the clinical diagnosis and to establish the genetic mechanism responsible for PWS, considering their consequences regarding the prognosis and genetic counseling.

TTHHAANNK K

YYOOU U

!!!!!!

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Genotype Phenotype Correlation In Prader Willi Syndrome