Microdel/dup Syndromes Flashcards
Features of 1p36 deletion syndrome?
- Dev delay
- Hypotonia
- Delayed/Absent speech
Variable in size (<1Mb to >10Mb)
Haploinsufficiency of a number of genes.
NB: 1p36 dup very rare!
Features of TAR )Thrombocytopenia Absent Radius) 1q21 proximal deletion (TAR syndrome)?
- 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.
Features of NRXN1 deletion (2p16.3)?
ASI:
- Autism
- Seizures
- Intellectual disability.
- Can be found in normal parents: reduced penetrance, variable expressivity.
- Depends on size/location of deletion!
Gene & features for Mowat Wilson deletion (2q22)?
X
- Gene: ZEB2
- Hirschsprung disease, Genitourinary abnormalities, dysmorphic features.
- Del in 15-20%, mutations more common!
Features of 2q37 deletion syndrome? Or Albright-like Syndrome!
- 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.
Features & critical gene for Wolf Hirschhorn Syndrome (4p16.3)?
- 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).
Features of Cri du chat syndrome (5p15.3)?
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
Critical gene & features of SOTOS Syndrome (5q35)?
Gene: haploinsuff of NSD1 gene
Features: Excessive growth in 1st 2-3years.
Large head, hands & feet
Seizures
Learning disability
Autosomal dominant inheritance.
Critical gene & features of Cornelia Lange Syndrome? 5p13.2
NIPBL gene
Features: Arched eyebrows that grow together
Growth retardation
Profound intellectual disability
Critical gene & features of Greig Cephalosyndactyly syndromes (7p13).
- GLI3
- Developmental problems affecting the limbs, head & face, seizures, developmental delay & ID.
Features of Williams Syndrome (7q11.23)?
- ELN Gene, LCRs, NAHR.
- Most 1.5Mb (5% 1.8Mb), facial appearance: ‘pixie like’, small upturned nose, supravulular aortic stenosis. Hypercalcaemia, dev delay, hypotonia.
Features of mosaic T8 (Warkany Syndrome)?
- Variable phenotype: skeletal abnorm, facial features, prominent forehead, hypertelorism, LD, congenital anomalies (incl cardiacs/renal defects), deep creases in palms & soles.
Roberts Syndrome gene & features?
- ESCO2 Gene mutations
- Hypomelia (shortening of arms & legs)
- dysmorphism
- Cleft lip/palate, microcephaly
Premature centromere separation…
Features of CHARGE syndrome? 8q21!!!!
- 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
Features & genes for Langer Giedion Syndrome (8q23-q24)
- loss of TRPS & EXT1
- Exostoses (bone spur: formation of new bone on surface of bone)
- Sparse hair
- Skeletal abnormalities
Kleefstra syndrome, features & gene?
- 9q34.3
- Haploinsufficiency of EHMT1 Gene
- Epilepsy, Self harming & abnormal sleep
Pulmonary infections, genital defects.
Features of 10q25-q26 deletion syndrome?
- Variable phenotype:
IUGR, feeding diff, hypotonia, renal abnorm, microcephaly. - Genes: EMX2 & FGFR2 (distinct facial features).
Feature of WAGR 11p13 deletion syndrome.
- 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.
Potocki-Shaffer Syndrome, genes & features?
- 11p11.2p12
- Exostoses (benign bone tumours)
- Intellectual disability
- Dev delay
- Micropenis In males
Genes: EXT2, ALX4
Jacobsen Syndrome (11q23.3-qter)
- includes FLI1
- IUGR, ADHD, abnormal platelet function.
Features of Pallister-Killian/ mosaic tetrasomy 12p?
- 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.
Noonan Syndrome! X mutations in RAS/MAPK pathway (KRAS: 12p12.2), PTPN11 (12q).
- Phenotype like TS!
- Short stature, Webber neck, sunken chest shape, dev delay, CHD.
Autosomal dominant, mainly de novo.
Patau Syndrome features?
- 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.
Retinoblastoma (13q14) RB1
- 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).
Paternal UPD14 (Wang Syndrome) phenotype?
- 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
Maternal UPD14 phenotype? Temple syndrome
- Pre & postnatal growth retardation
- low to normal ID
- Subtle dysmorphism, facial features.
- Phenotype generally mild, May go underdiagnosed.
15q11.2 deletion syndrome genes & phenotype?
- 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.
15q13.3 deletion syndrome CHRNA7?
- 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.
idic(15), 15q11-q13, phenotype?
- 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.
16p11.2 deletion syndrome?
- 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!
16p13.3 deletion syndrome, severe form of Rubinstein-Taybi syndrome!
- 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.
16p13.11 Duplication!
- 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!
Miller Dieker Syndrome 17p13.3
- 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
17p12 deletion: (HNPP)?
- 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!
Smith Magenis Syndrome 17p11.2
- 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.
Neurofibromatosis 1, 17p11.2
- 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.
Renal Cysts And Diabetes (RCAD) microdeletion 17q12
- 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.
17q21.31 deletion syndrome- Koolen de Vries.
- 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.
Charcot Marie tooth disease Type 1A, 17p12 Duplication?
- autosomal dominant. Variable expressivity.
- Distal muscle weakness & atrophy.
- PMP22 Duplication. 1.4Mb
- NAHR
Potocki-Lupski Syndrome 17p11.2?
- Failure to thrive, hypotonia, heart disease, behavioural problems, short stature. Sleep disordered breathing.
- 3.7Mb. Reciprocal dup of SMS region.
- NAHR
- RAI1 Gene Duplication!
Trisomy 18 Edward syndrome genotype?
- 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.
Mosaic T18 phenotype?
- Variable: phenotypically normal to complete T18!
- no correlation with % trisomy cells in either fibroblasts or leukocytes.
Tetrasomy 18p (isochromosome 18p)?
- 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.
Alagle Syndrome, 20p12, gene & phenotype?
- 97% due to Haploinsuff of JAG1
- 90% mutations, 7% deletions!
- Jaundice with conjugated hyperbirubinaemia, dysmorphic facies, CHD, ‘butterfly’ vertebrae.
Down syndrome!
- 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.
22q11.2 deletion syndrome.
- 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.
22q11.2 duplications?
- 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.
Cat eye syndrome +invdup(22)(pter-q11.2)
- Ocular coloboma (60% cases)
- Anal atresia
- Cardiovascular defects, dysmorphic features, dev delay.
- Caused by supernumerary bisatellited dicentric market chromosome of chr22 origin. Tetrasomy 22q11.
Phelan-McDermid Syndrome - distal 22q13 deletion.
- 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
Emanuel Syndrome - der(22)t(11;22)(q23.3;q11.2)
- 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.
