microdeletion syndromes Flashcards
3 clinical features associated with 16p11.2 deletion syndrome
macrocephaly, developmental delay, ASD, siezures (20%)
3 clinical features of Angelmans syndrome
Severe mental retardation or developmental delay
Absent speech
Happy smiling disposition with inappropriate laughter
Ataxic gait with flapping upheld arms (originally known as the “happy puppet” syndrome)
Microcephaly, large wide open mouth, prominent chin, deep set eyes & protruding tongue, tongue thrusting, drooling and mouthing
Love of water
Hypopigmentation
Hypo- and and hypertonia are also seen
Early onset epileptic seizures
gene location of PWS/AS
15q11.-q13
clinical features of PWS
Disorder of growth and development
Severe neonatal hypotonia (“floppy” baby) & feeding difficulties and/or failure to thrive in infancy
Hyperphagia resulting in obesity (diabetes & cardiac failure) in later infancy/early childhood
Mild-moderate MR, developmental delay & behavioural disorders (stubbornness, temper tantrums, poor peer interactions, unusual skill with jigsaw puzzles)
Characteristic facial features: almond-shaped eyes, low set ears, down-turned mouth, bilateral epicanthal folds
Short stature, small hands and feet
Hypogonadism in both males & females
Hypopigmentation
Skin picking
Features of 1p36 deletion syndrome
DD, dysmorphic, hypotonia, NO speech, behaviour probe-biting,tantrums, increase risk neural crest tumours, late Fontanelle closure
% 1p36 deletion syndrome that is inherited from balanced parental rea
20%
What locus does TAR map to?
1q21
How does TAR arise?
LCRs blocks X 4. Class 1: distal smaller and class 2: larger TAR and distal region
What syndromes are located at 1q21
TAR- proximal, distal 1q21 deletion, 1q21 duplication
Features of 1q21 dup syndrome
Macrocephaly, TOF incomplete penetrance
Candidate gene for head size in 1q21
HYDIN2. Del:small and dup:large
Phenotype of TAR
Absent radii WITH thumbs, cows milk intolerance, MDT
Genetics of TAR
Common 200kb deletion, 11genes, proposed 2nd hit required?
Where is mowat Wilson syndrome
2q22 deleted
Phenotype of mowat Wilson
Dysmorphic-open mouth, pointy chin, heart abns, aGenesis corpus callosum, Genito urinary problem
Mowat Wilson candidate gene
ZEB2. Mutations and deletions,2% gene disruption due to Chr rea. Most de novo
Where is Albright like syndrome located and what causes it (del/dup)?
2q37 (deletion)
Albright like syndrome candidate gene
Hdac4
Phenotype of Albright like syndrome
DD, autism,behavioural, dysmorphic, skeletal abns,GR. Phenotype variable and not correlate with deletion size
Features of 2q37 duplication
No dysmorphism and normal IQ
Genetics of ALports syndrome (hereditary nephritis)
X linked col4a5 mutation, or autosomal recessive col4a3 and col4a4 mutations (Chr 2). Genes involved in collagen biosynthesis
Phenotype of alports
Kidney disease, hearing loss, eyes-cataracts, bloody urine and protein in urine.
What does VHL stand for?
Von hippel lindau
Locus for VHL
3p25-26
Origins of WHS
90% are de novo. Deletions 55%, unbalced translocation 40-45%, complex rea in few. Can be Inherited from female carriers of t(4;8)(p16.3;p23). Others male derived.
Phenotype of WHS
Dysmorphism Greek warrior helmet, GR, seizures, MR, psychomotor delay
Is there a correlation of deletion size and phenotype severity
Increase size usually = increased severity. Arrays have identified more due to cryptic unbalanced reas which may explain variability south et al 2008
Genes in WHSCR and phenotype links
Whsc1 (face, GR)and letm (seizures)
Incidence of cri du chat
1/50,000
Where is cri du chat critical region
5p15.3 -15.2
What micro deletion is at 7q11.23
Williams
Incidence of Willian’s syndrome
1/10,000
Key gene in ws deletions
Eln - elastin
Where is SOTOS (cerebral gigantism)
5q35
Inheritance pattern of SOTOS
Autosomal dominant
Genetic abnormalities seen in SOTOS
95% de novo. Mainly mutations but is a recurrent Japanese 1.9Mb deletion.
Phenotype of SOTOS
Excessive growth up to age 3, macro exhale large hands and feet, increased bone age, mild-severe LD, cranial abns, large long skull, high bossed forehead
Where is the Twist gene and what is associated syndrome
7p21.1 involved in saethre chotzen syndrome. Point mutations or deletions seen- inc penetrance
Phenotype saethre chotzen syndrome
Skull defect prem fusion of cranial bones which prevents normal growth and results in odd shape/asymmetric skull, normal IQ
Where is shfm ectrodactyly locus
7q21.3
Where is shh gene located and what do defects in it cause
7q36, holoprosencephaly
Where are OR gene clusters
8p23.1
Why is there such a high incidence of OR reas?
Repd (distal rpt) and repp (prox repeat) flank 5Mb region
Which genes associated with langer Gideon
Trsp1 and ext1 (multiple exotoses type1)
CDC phenotype
Cat cry microcephaoy seizure severe mr fertile hypotonia
Where is region deleted in Alfi’s syndrome
9p22.3
Phenotype of Alfi’s syndrome
Trigonocephaly, severe speech probs, mr, abn genitalia dysmorphic
Where is DGS-2
10p13
Phenotype of DGS-2
More severe than DGS. Hypoglycaemia, absent thymus-> T cell deficit, heart, ,male abn genitalia, mr, dysmorphism
Percentages of different types I
Of patau syndrome
75%: NDJ. Most mat meiosis 1 or mitotic. 20% unbalanced rob. 5% mosaic
Phenotype 13q14 deletion syndrome
Depends on size. Retinoblastoma, DD, speech language delay, dysmorphic
What is wang syndrome
Upd14 pat. More severe than mat upd14. Dysmorphic, mr, abdominal wall defect
Where is rubenstein taybi locus and associated gene
16p13.3. CREBBP
R-T phenotype
Generalised disregulation of gene expression of CREBBP causes multiple abns. Short, mr, dysmorphic, broad thumb/big toe, increased cancer risk
Miller dieker locus
17p13.3
SMS locus
17p11.2
Duplication of 17p11.2
Potaki-lupski. ID by aCGH in 2008
Phenotype potaki-lupski
DD, autism, FTT
Cyto abnormality seen in Emmanuel syndrome
Der(22)t(11;22)(q23.3:q11.2)
Phenotype of CAt eye syndrome
Ocular Coloboma, anal abns, septal heart defects, dysmorphism,skin tags. No obvious differences between types 1 and 2
Region associated with phelan-mcdermid syndrome
22q13 deletion
Which are the 2 most common terminal micro deletions?
1p36 and then 22q13
Phenotype of 22q13 deletion
Dysmorphic, DD.speech delay, hypotonia
