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Microdeletion- Duplications Syndromes > Microdel/dup Syndromes > Flashcards

Microdel/dup Syndromes Flashcards

1
Q

Features of 1p36 deletion syndrome?

A
  • Dev delay
  • Hypotonia
  • Delayed/Absent speech

Variable in size (<1Mb to >10Mb)
Haploinsufficiency of a number of genes.

NB: 1p36 dup very rare!

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2
Q

Features of TAR )Thrombocytopenia Absent Radius) 1q21 proximal deletion (TAR syndrome)?

A
  • Absent radii (bones in forearms) with presence of thumbed (unlike FA).
  • Early onset Thrombocytopenia that tends to resolve in childhood!
  • Can have short/Absent ulna (other bone in forearm).
  • approx 200kb 11 genes incl RBM8A.
  • TAR is autosomal recessive, maj. patients have deletion & point motion on other allele.
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3
Q

Features of NRXN1 deletion (2p16.3)?

A

ASI:

  • Autism
  • Seizures
  • Intellectual disability.
  • Can be found in normal parents: reduced penetrance, variable expressivity.
  • Depends on size/location of deletion!
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4
Q

Gene & features for Mowat Wilson deletion (2q22)?

X

A
  • Gene: ZEB2
  • Hirschsprung disease, Genitourinary abnormalities, dysmorphic features.
  • Del in 15-20%, mutations more common!
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5
Q

Features of 2q37 deletion syndrome? Or Albright-like Syndrome!

A
  • Dev. Delay
  • Hypotonia
  • Growth delay!

Phenotype Highly variable, very mild features to quite severe! (Size does not correlate with severity…)
- No common breakpoints: due to non-homologous recombination.

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6
Q

Features & critical gene for Wolf Hirschhorn Syndrome (4p16.3)?

A
  • Facial features, ‘Greek-warrior helmet (hypertelorism, high forehead), microcephaly.
  • Growth delay
  • Mental retardation & seizures!

Gene: WHSCR-2 (redefined from originally believed critical region WHSCR-1)
- Generally larger deletion, more severe phenotype!

~90% de novo.
- can arise from unbalanced translocations.
Genes: WHSCR2, WHSCR1 & LETM1(seizures).

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7
Q

Features of Cri du chat syndrome (5p15.3)?

A

Genes: hTERT, CTNND2, SEMA5A

Features: Cat like cry due to abnormal larynx

  • feeding difficulties
  • Cardiac defects
  • Mental retardation

80% de novo, Del size 5-40Mb

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8
Q

Critical gene & features of SOTOS Syndrome (5q35)?

A

Gene: haploinsuff of NSD1 gene

Features: Excessive growth in 1st 2-3years.
Large head, hands & feet
Seizures
Learning disability

Autosomal dominant inheritance.

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9
Q

Critical gene & features of Cornelia Lange Syndrome? 5p13.2

A

NIPBL gene

Features: Arched eyebrows that grow together
Growth retardation
Profound intellectual disability

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10
Q

Critical gene & features of Greig Cephalosyndactyly syndromes (7p13).

A
  • GLI3

- Developmental problems affecting the limbs, head & face, seizures, developmental delay & ID.

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11
Q

Features of Williams Syndrome (7q11.23)?

A
  • ELN Gene, LCRs, NAHR.
  • Most 1.5Mb (5% 1.8Mb), facial appearance: ‘pixie like’, small upturned nose, supravulular aortic stenosis. Hypercalcaemia, dev delay, hypotonia.
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12
Q

Features of mosaic T8 (Warkany Syndrome)?

A
  • Variable phenotype: skeletal abnorm, facial features, prominent forehead, hypertelorism, LD, congenital anomalies (incl cardiacs/renal defects), deep creases in palms & soles.
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13
Q

Roberts Syndrome gene & features?

A
  • ESCO2 Gene mutations
  • Hypomelia (shortening of arms & legs)
  • dysmorphism
  • Cleft lip/palate, microcephaly

Premature centromere separation…

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14
Q

Features of CHARGE syndrome? 8q21!!!!

A
  • 30-40% deletion of CHD7 gene
  • C: Coloboma
  • H: Congenital heart defects
  • A: choanal Atresia (narrowing of nasal airway by tissue).
  • R: Retarded growth & dev
  • G: Genital anomalies
  • E: Ear anomalies assoc. with deafness
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15
Q

Features & genes for Langer Giedion Syndrome (8q23-q24)

A
  • loss of TRPS & EXT1
  • Exostoses (bone spur: formation of new bone on surface of bone)
  • Sparse hair
  • Skeletal abnormalities
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16
Q

Kleefstra syndrome, features & gene?

A
  • 9q34.3
  • Haploinsufficiency of EHMT1 Gene
  • Epilepsy, Self harming & abnormal sleep
    Pulmonary infections, genital defects.
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17
Q

Features of 10q25-q26 deletion syndrome?

A
  • Variable phenotype:
    IUGR, feeding diff, hypotonia, renal abnorm, microcephaly.
  • Genes: EMX2 & FGFR2 (distinct facial features).
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18
Q

Feature of WAGR 11p13 deletion syndrome.

A
  • W: Wilms tumour
  • A: Aniridia
  • G: Genitourinary anomalies
  • mental Retardation
  • Wilms tumour: 45-60% cases, requires 2 hits to WT1 allele to cause cancer.
    Aniridia: PAX6 Del

Genes: WT1 & PAX6. Contiguous gene del syndrome.

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19
Q

Potocki-Shaffer Syndrome, genes & features?

A
  • 11p11.2p12
  • Exostoses (benign bone tumours)
  • Intellectual disability
  • Dev delay
  • Micropenis In males
    Genes: EXT2, ALX4
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20
Q

Jacobsen Syndrome (11q23.3-qter)

A
  • includes FLI1

- IUGR, ADHD, abnormal platelet function.

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21
Q

Features of Pallister-Killian/ mosaic tetrasomy 12p?

A
  • Variable Phenotype:
  • Prenatal: Diaphragmatic hernia
  • Postnatal: Hypotonia, Speech delay/absence, Dysmorphic face, Hypo/hyper skin pigmentation, seizures.

Tissue specific detection!

  • rarely seen in cultured blood lymphocytes.
  • Seen In amniotic fluid & skin fibroblasts.
  • failure to detect in blood ? Instability of the i(12p) at mitosis & i(12p) being lost due to huge turnover rate of these cells.
  • Using aCGH gains of 12phave been detected in blood!

Genetics:

  • mostly maternal origin., increase with MA. Occurs de novo.
  • Meiosis II origin for the majority of patients.
22
Q

Noonan Syndrome! X mutations in RAS/MAPK pathway (KRAS: 12p12.2), PTPN11 (12q).

A
  • Phenotype like TS!
  • Short stature, Webber neck, sunken chest shape, dev delay, CHD.

Autosomal dominant, mainly de novo.

23
Q

Patau Syndrome features?

A
  • Prenatal: Holoprosencephaly (failure of forebrain to divide), polydactyly, cystic kidneys.
  • Postnatal: Holoprosencephaly, microcephaly, eye abnormalities, cleft lip/palate, severe MR, polydactyly.
  • 75% due to 47,+13
  • 20% unbalanced Robertsonian, majority are de novo.
24
Q

Retinoblastoma (13q14) RB1

A
  • mutations of RB1 gene
  • Cancer develops in sensory cells of retina.
  • 2 types: Bilateral: usually presents <1
    Unilateral: 24-30mths.

Phenotype: Deterioration of vision, red itrated eyes, squint.

  • Recessive condition (2 altered copies of RB1).
  • 40% Germinal (all cells incl reproductive), more likely Bilateral.
  • 60% Non-germline: occurs only in eye. No family history, more likely unilateral retinoblastoma).
25
Q

Paternal UPD14 (Wang Syndrome) phenotype?

A
  • polyhydramnios & premature labour.
  • low birth weight, thoracic & abdominal wall defects, small chest & bell shaped rib cage (coat hanger ribs on X-ray) leading to underdeveloped lungs & respiratory problems.
  • moderate-severe LD
  • Subtle dysmorphism
26
Q

Maternal UPD14 phenotype? Temple syndrome

A
  • Pre & postnatal growth retardation
  • low to normal ID
  • Subtle dysmorphism, facial features.
  • Phenotype generally mild, May go underdiagnosed.
27
Q

15q11.2 deletion syndrome genes & phenotype?

A
  • 4 genes that are not imprinted: TUBGC5, NIPA1, NIPA2, CYFIP1.
  • BP1- BP2
  • Often inherited from an unaffected or less affected parent.
  • May increase Susceptibility to neuropsychiatric or neurodevelopmental problems: speech delay, autism spectrum disorder, obsessive-compulsive disorder & possibly seizures.
  • Many patients with deletion have no apparent physical, learning of behavioural diff.
28
Q

15q13.3 deletion syndrome CHRNA7?

A
  • Deletion Ben BP4&BP5 of PWACR.
  • Neurodevelopmental. Problems, incomplete penetrance.
  • Wide spectrum of neurodevelopmental disorders with no or subtle dysmorphic features.
  • Dev delay (mainly speech), epilepsy/seizures, autism, impulsive/aggressive behaviour.
  • BO4&BP5 are in inverted orientation in proportion of population, facilitated NAHR, resulting in genomic rearrangements.
  • Haploinsuff of CHRNA7 might be responsibly for most of neurodevelopmental disorders assoc with deletion.
  • 25% de novo, 75% inherited in AD manner, incomplete penetrance.
  • Not all carriers will dev Syndrome.
29
Q

idic(15), 15q11-q13, phenotype?

A
  • HADE: Hypotonia, autism, dev delay, epilepsy.
  • If idic(15) is very small & does not contain PWACR, usually will not have any clinical impact.
  • Approx. 50% of SMC are idic(15)
  • Appear bisatellited, pseudoscientific.
  • most patients have 4 copies of critical 15q11-13 region.
30
Q

16p11.2 deletion syndrome?

A
  • 600kb, >25 genes, SH2B1 - obesity link
  • mediated by NAHR
  • Speech & language delay,seizures, autism, Macrocephaly, obesity [~50%].

16p11. 2 duplication:
- Behaviour problems,ADHD, seizures, Microcephaly.

Phenotypes are variable, incomplete penetrance! Both del & duplications May be inherited from parents with milder phenotype or who are asymptomatic!

31
Q

16p13.3 deletion syndrome, severe form of Rubinstein-Taybi syndrome!

A
  • 40kb-3Mb deletion, incl 5’ end of CREBBP Gene.
  • Phenotype: Classical Rubinstein Taybi: short stature, ID, facial features.
  • increased risk of dev noncancerous & cancerous tumours (brain & leukaemia)
  • deletion show more severe pheno than mutations: may also incl FTT, Seizures, life-threatening malformations in addition to Rubinstein Taybi phenotype. In all reported cases, died in infancy!
  • ~20% deletions (maj mutations).

16p13. 3 Duplication:
- Inclu CREBBP Gene
- mechanism ? Non-homologous end joining!
- Mild to mid ID with marked speech problems, limb anomalies (clubfoot), growth delay.
- inherited from normal parents.

32
Q

16p13.11 Duplication!

A
  • 9 genes incl MYH11
  • susceptibility to AD familial aortic aneurysms!
  • incomplete penetrance, dup in normal controls.

16p13. 11 deletion:
- Incl LIS1 Gene (PAFAH1B1).
- associated with epilepsy. Susceptibilityto ID, autism, schizophrenia!

33
Q

Miller Dieker Syndrome 17p13.3

A
  • features: lissencephaly (PAFAH1B1, LSI1 Gene)- ‘smooth Brain’, brain malformations cause severe ID, dev delay, seizures, microcephaly, cardiac abnorm, rarely survive beyond childhood!
  • incl 6 other genes, YWHAE
34
Q

17p12 deletion: (HNPP)?

A
  • Hereditary neuropathy with liability to pressure palsies.
  • 16p12 deletion, PMP22 gene
  • Numbness of nerves following pressure on nerves. Age of onset 15-20yr.
  • deafness
  • deletion or mutation leads to abnormal myelination of peripheral nerves. 80% deletions.
  • Often inherited!
35
Q

Smith Magenis Syndrome 17p11.2

A
  • ID, delayed doeech & language, sleep disturbances & behavioural problems (temper tantrums), self harming, skin picking, biting.
  • Hoarse voice
  • 90% interstitial del,incl RAI1 Gene.
  • Haploinsuff of RAI1 responsible for most features (behavioural, craniofacial).
  • Nearly all de novo.
36
Q

Neurofibromatosis 1, 17p11.2

A
  • Contiguous deletion syndrome encompassing NF1.
  • 5-20% have 1.4Mb deletion of 17p11.2.
  • Mental retardation, dev delay, multiple neurofibromas, dysmorphism, increased risk of peripheral nerve sheath rumours.
  • NAHR Btn LCRS, loss of 14genes. Type 1: 1.4Mb
  • Type 2: 10-20%, 1.2Mb. Type 3 variable in size.
37
Q

Renal Cysts And Diabetes (RCAD) microdeletion 17q12

A
  • Non diabetic renal disease resulting from abnormal kidney development.
  • renal disease is variable: incl renal cysts, small kidney, horseshoe kidney develop in early life.
  • Diabetes diagnosed 10-40yr, can be treated with insulin.
  • Haploinsuff of HNF1B (prev TCF2) is causative of RCAD. 1.5Mb deletion.
  • Possible assoc with LD/autism.
  • Autosomal dominant disorder.
38
Q

17q21.31 deletion syndrome- Koolen de Vries.

A
  • Features: dev delay, hypotonia, cardiac defects, seizures.
  • autosomal dominant. Almost all de novo.
  • Recurrent 500kb deletion at 17q21.31, KANSL1 Gene.
  • LCRs responsible for rearrangement: 900kb inversion polymorphism At 17q21.31 In 20% population. Unaffected parents have inversion polymorphism (H2 haplotype). Can undergo deletion rearrangement via NAHR.
39
Q

Charcot Marie tooth disease Type 1A, 17p12 Duplication?

A
  • autosomal dominant. Variable expressivity.
  • Distal muscle weakness & atrophy.
  • PMP22 Duplication. 1.4Mb
  • NAHR
40
Q

Potocki-Lupski Syndrome 17p11.2?

A
  • Failure to thrive, hypotonia, heart disease, behavioural problems, short stature. Sleep disordered breathing.
  • 3.7Mb. Reciprocal dup of SMS region.
  • NAHR
  • RAI1 Gene Duplication!
41
Q

Trisomy 18 Edward syndrome genotype?

A
  • 1:6,000 live births
  • Maj cause of death: cardiac failure, upper airway obstruction.
  • 90% trisomies due to non-disjunction at maternal meiosis.
  • 5% T18s are mosaic!
  • IUGR, microcephaly, cleft lip, rocker bottom feet, overlapping fingers, clenched fist, severe dev delay, heart defects (ventricular septal defect, apnoea, seizures.
42
Q

Mosaic T18 phenotype?

A
  • Variable: phenotypically normal to complete T18!

- no correlation with % trisomy cells in either fibroblasts or leukocytes.

43
Q

Tetrasomy 18p (isochromosome 18p)?

A
  • low birth weight, feeding diff, hypotonia, dev delay, breathing diff, strabismus.
  • most de novo. Most maternal origin.
  • arises: non-disjunction at maternal meiosis II & centric misdivision (like i(12p).) Mayernal she may play a role.
44
Q

Alagle Syndrome, 20p12, gene & phenotype?

A
  • 97% due to Haploinsuff of JAG1
  • 90% mutations, 7% deletions!
  • Jaundice with conjugated hyperbirubinaemia, dysmorphic facies, CHD, ‘butterfly’ vertebrae.
45
Q

Down syndrome!

A
  • 1:750, 70% non/disjunction maternal meiosis I, 20% maternal meiosis Ii.
  • 2% mosaic, anaphase lag in triatomic conceptus, nondisjunction in normal conceptus.
  • ID, characteristic face (epicanthic folds, upward slanting pal pearl fissures, flattened nose, protruding tongue), single Palmer crease.
  • Transient leukaemia (10%) at birth.

21q22. 11q22.13: Braddock-Carey Syndrome
- Deletion that incl RUNX1. Features: congenital thrombocytopenia, dev delay, facial dysmorphism.

46
Q

22q11.2 deletion syndrome.

A
  • 90% patients 3Mb deletion, maj de novo.
  • TBX1/HIRA
  • Hypocalcaemia, recurrent infections (absence of thymus), tetralogy of fallot, cleft palate, Learning difficulties.
  • 1:4,000/6,000.

Distal 22q11.2 deletions:

  • Dev delay, short stature, dysmorphism.
  • NAHR.
47
Q

22q11.2 duplications?

A
  • freq half that of deletions.
  • Phenotype: milder than deletions. Variable, mild LD, heart defects, hypernasal speech, behavioural diff, schizophrenia & ASD.
  • some patients no phenotypic effect. Often inherited. 3Mb or1.5Mb.
48
Q

Cat eye syndrome +invdup(22)(pter-q11.2)

A
  • Ocular coloboma (60% cases)
  • Anal atresia
  • Cardiovascular defects, dysmorphic features, dev delay.
  • Caused by supernumerary bisatellited dicentric market chromosome of chr22 origin. Tetrasomy 22q11.
49
Q

Phelan-McDermid Syndrome - distal 22q13 deletion.

A
  • Dev delay incl speech delay, hypotonia, dysmorphism (long eyelashes), autism.
  • most cases have loss of FISH probe ARSA.
  • 75% de novo. 20% result of unbalanced structural rearrangements.
  • <1% mutations within SHANK3 gene
50
Q

Emanuel Syndrome - der(22)t(11;22)(q23.3;q11.2)

A
  • Heart defects (VSD), cleft palate, renal abnorm, Genitourinary tract malformations.
    Dysmorphism, dev delay.
  • 3:1 malsegregation (tertiary trisomy) of t(11;22)(q23.3;q11.2), most common translocation in humans.
  • Recurrence risk: 3.7% for females
  • <0.7% for males.

Microdeletion- Duplications Syndromes (1 decks)

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