Microdeletions, Microduplications and Contiguous Gene Disorders

Question 1

________ ________ __________ is a small segment of extra or missing DNA

Answer 1

copy number variation (CNV)

Question 2

_________ is 0 or 1 copy of the region

Answer 2

deletion (loss)

Question 3

__________ is 3 or more copies of the region

Answer 3

duplication (gain)

Question 4

_________ deletions/duplications are 3-5 Mb and can be seen on a karyotype

Answer 4

classic

Question 5

___________ are smaller than 3 Mb and can be detected by FISH, CMA etc

Answer 5

microdeletions

Question 6

___________ is when one copy of the gene is not sufficient

Answer 6

haploinsufficiency

Question 7

_________________ is when three copies of the gene is too much

Answer 7

triplosensitivity

Question 8

Are deletions or duplications more likely to be pathogenic?

Answer 8

deletions

Question 9

___________/_________________ _____________ are disorders due to the deletion or duplication of two or more genes located in proximity to each other

Answer 9

Microdeletion/duplication syndromes

Question 10

_____________(acronym) causes 10-22% of structural rearrangements
Interchromosomal – between homologs
Intrachromosomal – between sister chromatids
Intrachromatid – within the same chromosome

Answer 10

NAHR- non-allelic homologous recombination
- repetitive sequences

Question 11

________________________ structural rearrangements between homologs

Answer 11

interchromosomal

Question 12

________________________ structural rearrangements between sister chromatids

Answer 12

intrachromosomal

Question 13

________________________ structural rearrangements within the same chromosome

Answer 13

intrachromatid

Question 14

Microdeletion/microduplication syndrome phenotype?

Answer 14

Developmental Delay
Intellectual Disability
Dysmorphism
Organ malformation

Question 15

Two examples of microdeletion syndrome?

Answer 15

RBM8A and TAR (thrombocytopenia absent radii syndrome)
Biotinidase deficiency

Question 16

Inheritance pattern of microdeletion syndrome?

Answer 16

De novo or autosomal dominant - 22q microdeletion syndrome

Question 17

4p deletion syndrome

Answer 17

Wolf-Hirschhorn syndrome

Question 18

5p deletion syndrome

Answer 18

Cri du Chat syndrome

Question 19

10p13 deletion syndrome

Answer 19

DiGeorge II syndrome

Question 19

7q11.2 deletion syndrome

Answer 19

Williams (Williams-Beuren) syndrome

Question 20

15q11-q13 deletion syndromes

Answer 20

PWS/Angelman

Question 20

16p13.3 deletion

Answer 20

Rubinstein Taybi syndrome (CBP - creb binding protein)
#1 cause of autism spectrum disorder

Question 21

17p11.2 deletion

Answer 21

Smith Magenis syndrome

Question 22

17p11.2 duplication

Answer 22

Potocki/Lupski syndrome

Question 23

22q11.2-q11.23 deletion or duplication?

Answer 23

22q11.2-q11.23 deletion or duplication syndrome

Question 24

Most common microdeletion syndrome?

Answer 24

22q11.2 syndrome

Question 25

Four genes in 22q11.2 region of deletion

Answer 25

TBX1 – implicated in cardiac- VSD, Tetralogy of Fallot, Aortic arch anomalies, palate defects COMT – evidence that may be critical gene w/ regard to the psychiatric problems SNAP29 – implicated in cutaneous and other atypical findings seen in some individuals w/ deletion >> Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome PROHD >> risk psychiatric illness Jacquet 2002 PMID 12217952

Question 26

22q11.2 inheritance

Answer 26

93% de novo 7% familial

Question 27

3 main disorders of infancy with heart defects

Answer 27

1. Aneuploidy 2. Noonan syndrome 3. 22q11.2 deletion syndrome

Question 28

22q11.2 deletion phenotype faces?

Answer 28

Eye structures Epicanthal folds Hooded eyelids Dark/red under-eyes (suborbital congestion) Nose structure Broad nasal bridge Tubular nose shape Bulbous nasal tip Nostril sidewalls underdeveloped (hypoplastic alae nasi) Ear Structure Small or protuberant ears Thick/overfolded helix Low-set, posterior rotated Preauricular pits/tags Boney structures Micrognathia Malar flattening (underdeveloped cheekbones) Small Teeth Other Asymmetrical crying face Downturned mouth

Question 29

22q11.2 deletion critical gene responsible for congenital heart disease (VSD, TOF), abnormal facies, thymic aplasia and hypocalcemia?

Answer 29

T-box 1 (TBX1)

Question 30

22q11.2 deletion syndrome has _____________ penetrance and __________ expressivity

Answer 30

complete penetrance, variable expressivity

Question 31

FISH probe for 22q11.2 deletion syndrome? ** CMA better **

Answer 31

TUPLE1/HIRA (Histone cell cycle Regulation defective S. cerevisiae homolog of A)

Question 32

DiGeorge syndrome II gene region?

Answer 32

10p14-p13

Question 33

Gene for autosomal dominant CHARGE syndrome?

Answer 33

CHD7 Chromodomain-helicase-DNA-binding protein 7

Question 34

CHARGE syndrome phenotype?

Answer 34

Coloboma Heart defects Atresia of choanae Retardation of growth and development Genital hypoplasia Ear abnormalities

Question 35

AR conditions associated with 22q11.2 deletion syndrome?

Answer 35

SNAP29 -Cerdnik syndrome GP1BB - Bernard Soulier syndrome CDC45- craniosynostosis SCARF2 - Van den Ende -Gupta syndrome TANGO2 - encephalomyopathic and neurodegeneration

Question 36

22q11.2 duplication syndrome phenotype

Answer 36

milder than deletion and variable, inherited from parent -heart defects -urogenital anomalies -velopharyngeal insufficiency with or without cleft palate -feeding problems -hearing impairment -facial dysmorphism

Question 37

der(22)t(11;22) syndrome

Answer 37

Emanuel syndrome

Question 38

inv dup of 22

Answer 38

Cat eye syndrome

Question 39

Incidence of 22q11.2 deletion syndrome

Answer 39

1 in 4,000 (to 6,000)

Question 40

Incidence of 4p16 deletion syndrome?

Answer 40

1 in 50,000 births

Question 41

Three genes of 4p16 deletion (Wolf Hirschhorn) syndrome?

Answer 41

WHSC1, LETM1 and MSX1 - functions largely unknown in development

Question 41

4p16 deletion (Wolf Hirschhorn) syndrome phenotype

Answer 41

Greek warrior helmet colobomas CHDs GU ID, seizures, microcephaly

Question 42

4p16 deletion (Wolf Hirschhorn) syndrome inheritance?

Answer 42

De novo

Question 43

5p microdeletion syndrome incidence?

Answer 43

1 in 50,000 (15,000 - 50,000)

Question 44

5p microdeletion syndrome phenotype?

Answer 44

Laryngeal malformation - Cri du Chat - 5p15.3 Hypotonia Microcephaly Facial features Cleft palate/lip Male genital anomalies - cryptorchidism, hypospadias Renal anomalies Syndactyly

Question 45

5p microdeletion syndrome facial features?

Answer 45

*Head Microcephaly Round face Micrognathia *Eyes Hypertelorism Epicanthal folds Down slanting palpebral fissures *Ears Low set or malformed ears *Mouth Dropped-jaw/open-mouth expression (secondary to facial laxity) Malocclusion of the teeth

Question 46

In 80% of the 5p microdeletion cases, there was __________ (maternal/paternal) inheritance?

Answer 46

paternal

Question 47

Incidence of 7q11.23 microdeletion syndrome

Answer 47

1 in 10,000 1 in 1750 with inversion Williams (-Beuren) syndrome

Question 48

Critical gene in 7q11.23 microdeletion syndrome?

Answer 48

ELN - elastin

Question 49

Phenotype for 7q11.23 microdeletion syndrome?

Answer 49

supravalvular aortic stenosis (SVAS) autosomal dominant cutis laxa stellate/lacy iris broad forehead, bitemporal narrowness hoarse voice hypercalcemia, hypercalciuria ID Strengths in short term memory Deficits in visuospatial memory Overfriendliness, empathy, anxiety, ADD

Question 50

Inheritance for 7q11.23 microdeletion syndrome?

Answer 50

De novo

Question 51

7q11.23 microduplication syndrome phenotype?

Answer 51

Social phobia/anxiety Language delay with mild visuospatial impairment Macrocephaly Dilation of ascending aorta Seizures and hypotonia

Question 52

17p12 microdeletion vs microduplication syndromes? *bonus

Answer 52

microdeletion - HNPP - PMP22 microduplication - CMT - PMP22

Question 53

17p11.2 microdeletion vs microduplication syndromes?

Answer 53

microdeletion - Smith Magenis syndrome microduplication - Potocki Lupski syndrome

Question 54

Critical gene for 17p11.2 microdeletion/microduplication syndromes?

Answer 54

RAI1 -retinoic acid inducer gene

Question 55

Incidence of 17p11.2 microdeletion syndrome?

Answer 55

1 in 25,000 (to 15,000) Smith Magenis syndrome

Question 56

Phenotype of 17p11.2 microdeletion syndrome?

Answer 56

Tented upper lip, deep set eyes, coarse features Inverted sleep pattern Intolerance to ambient noise autism, self hug Onychotillomania Dermatillomania

Question 57

Inheritance of of 17p11.2 microdeletion syndrome?

Answer 57

De novo (almost all)

Question 58

Incidence of 17p11.2 microduplication syndrome?

Answer 58

1 in 25,000 Potocki Lupski syndrome

Question 59

Phenotype of of 17p11.2 microduplication syndrome?

Answer 59

Hypotonia/FTT Sleep apnea autistic broad forehead triangular to oval face heart defects