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Prader Willi syndrome and Genetics and differentials
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.
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.
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”
21.
22.
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)