This document discusses Prader-Willi syndrome (PWS), including its history, genetics, causes, diagnostic features, genetic testing, and recurrence risk. PWS is caused by the loss of expression of paternal genes in the 15q11-q13 region, which can occur due to deletions, uniparental disomy, or imprinting defects. Key diagnostic features include hypotonia, developmental delay, hypogonadism, hyperphagia leading to obesity, and a characteristic facial gestalt. Genetic testing methods like methylation studies, FISH, CMA, and sequencing can help determine the specific genetic cause. The recurrence risk is usually low but increases to 50% for familial imprinting center defects

1. Dr Ebin Roshan Paul
Assistant Professor & Clinical Geneticist
PKDAS IMS Ottapalam Kerala
Prader-Willi Syndrome

2. Prader Willi syndrome
 1887: Langdon Down  a “polysarcia” case
 1956: Prader described a series of cases
 1981: D H Ledbetter identified deletions between
15q11 and 15q13 and determined site of PWS
1680 by Juan Miranda

3. Mendelian Inheritance
 Johann Gregor Mendel (1822-1884)- Father of
Genetics
 “Law of inheritance”  1) The Law of Segregation
2) The Law of Independent
Assortment
3) The Law of Dominance

4. Law of Dominance
 Mendelian “Law of dominance” : Both alleles from the
parent are equally expressed, some are dominant while
others are recessive; dominant allele will display the
effect, irrespective parent of origin.

5. “Non-Mendelian inheritance”
 Incomplete dominance
 Co-dominance
 Polygenic traits
 Mosaicism
 Genomic imprinting

6. Genetics of Imprinting
 Imprinting – Non Mendelian Inheritance; expression of gene
depend on “parent of origin” rather than dominance.
 < 1 % our whole genome is imprinted.
 Chrm15q11 – q13 contains an area called PWScr.
 This region is expressed only on paternally inherited
chromosome and corresponding area on maternally inherited
chromosome is silenced.

7. Prader-Willi and Angelman
Syndrome
(Chromosome 15q11.2-q13)

8. PWS-AS Critical Region
 proximal long arm of chromosome 15 (15q11.2-q13)
 4 distinct regions delineated by 3 common deletion breakpoints
(BP)
 1) Non imprinted region between BP1 and BP2 contain 4 genes
(biparental expression)  NIPA 1
 NIPA 2
 CYF1P1
 GCP5

9.  2) PWS region  paternally only expressed region.
Maternal contributions of genes here are silenced by
epigenetic factors.
genes are  5 genes code for polypeptide
 C15orf2
 a cluster of small nucleolar RNA
(snoRNA)
 several antisense transcripts

10.  3) AS region  preferentially maternal expressed
genes
Genes  UBE3A
 ATP10A

11.  4) distal non imprinted region followed by common
distal BP3
Genes  3 GABA receptor genes
 OCA 2
 HERC2

12. Causes of PWS
Loss of paternal inherited area in critical area
 70-80% : microdeletions in paternal copy
 20-25% : maternal uniparental disomy (mUPD)
 1% : silencing of paternal alleles due to IC (imprinting
center) defect in paternal chromosome
 <1%: rearrangement involving chromosome 15q with other
chromosomes

13. Uniparental Disomy (UPD)
 Occurs when both chromosomes of a pair arise from a
single parent, nothing is inherited from other parent.
 Particularly important in imprinted areas.
 In PWS if maternal UPD is present in (15q11.2 –q13),
there wont be any paternal alleles to express and both
maternal alleles will be silenced of imprinting.

14. (3n) wont survive so one of the
chromosome is lost during division,
so 33% chance to produce a UPD
(n) will not survive so
It will take duplication t
make (2n)
(3n)
(2n) (2n) (2n)

15. Imprinting Center (IC) defect
PWS
 Paternal expressed alleles  unmethylated
 Maternal silenced alleles  methylated
 IC control the expression of genes in 15q11-q13, has 2 critical part
 PWS-SRO and AS-SRO
 AS-SRO is needed for maternal imprinting and PWS-SRO needed
for paternal imprinting
 If paternal IC is having microdeletions or aberrant methylation will
produce PWS
 Familial IC deletions  50% recurrence risk

16. Diagnostic Handles
 Hypotonia (100%) : universal finding in PWS
Antenatal Postnatal
Reduced FM
Abnormal positions
Assisted delivery
C section
Feeding issues
Weak cry
Poor suck
Spontaneous arousal
FTT

17.  Developmental delay(90-100%) , Language and IQ
delay
 Classical transition of PWS from “feeding
issues/FTT” to “Hyperphagia and Obesity” 
occurs in phase 3 of nutrition and hypothalamus
induced change.
 Hypogonadism: both sexes ( genital hypoplasia, small
penis, infertility, incomplete pubertal development )
 Cryptorchidism – 100%

18.  Short stature- birth length usually normal followed by
fall in GV 2-3 years and final height <2SD.
 Hyperphagia: “food seeking behaviour”, hoarding
foods, eating inedible, stealing food, night awakening
for food.
 Obesity: Central obesity follows after a period of FTT
in infancy. Late onset and preadolescent period onset
obesity not fit in to criteria.
Behaviour issues like self mutilation, skin picking noted

19.  small hands and feet with straight borders of the ulnar
side of the hands and inner side of the legs

20. Facial Gestalt
 Narrow bifrontal diameter
 Almond shaped palpebral fissure
 Narrow nasal bridge
 Thin vermilion of upper lip
 Down turned corner of mouth
 Small mouth
“facial features slowly evolve over time”

23. Recurrence Risk
 Usually <1%
 But when associated with familial chromosomal
rearrangement or IC (imprinting center) defect  50%

24. Genetic testing - PWS
 DNA methylation study  ideal first test in suspected PWS.
In normal individual one methylated (maternal) and one
unmethylated (paternal ) copy seen.
If only methylated copy seen we can suspect PWS
 FISH deletions, limited to AS/PWS region
Or
 CMA  deletions, better than FISH (give details about deletion,
about remainder of genome, higher detection frequency and
pick up microdeletions)

25.  DNA polymorphism  differentiate UPD and ID
If biparental inheritance seen  Imprinting defect
If maternal only seen  UPD
 DNA sequencing  very specific role in ID to
differentiate IC deletion from epimutation, limited to a
region of <4.3 kb in the PWS IC smallest region
of deletion overlap (SRO)

26. FISH – deletion in PWSCR

27. MLPA- Gel electrophoresis

28. GeneReviews® [Internet]

30. Molecular Result

31. Standard testing PWS