Chromosome Disorders

Question 1

Ways of identifying genes?

Answer 1

G-Banding

PFGE & FISH

DNA sequencing

X-Ray Crystollography

Question 2

What occurs in mosai form?

Answer 2

Numerical- aneuploidy (abnormal number of chromosomes)
autosome
sex chromosome
Structural
deletion
duplication
isochromosome
inversion- para/pericentric
ring chromosome

Question 3

origin of aneuploidy?

Answer 3

*Non-disjunction during gametogenesis
Meiosis 1 most common maternal
Meiosis 2 less common
*Post-zygotic non-disjunction
Mitosis less common
*Gonadal mosaicism ??

Question 4

Non-disjunction in aneuploidy?

Answer 4

Failure of chromosomes to separate symmetrically during cell division
Meiosis
Meiosis I (MI) errors mis-segregation of homologous chromosomes
Heterodisomy
Meiosis II (MII) errors mis-segregation of chromatids
Isodisomy

Question 5

discuss meiosis and spindle formation?

Answer 5

Meiosis and meiotic spindle formation in mammalian oocytes: Separate spindle formation at meiosis I and II; after fertilization there is a new mitotic spindle formation. Several proteins are involved in each spindle formation. Mutations in genes involved in the formation of spindle proteins are believed to take part in both meiotic and mitotic chromosome malsegregation- a major biological factor for aneuploidy

Question 6

2 hit hypothesis of non-disjuncton?

Answer 6

Abnormal bivalent & chiasma formation
Age dependent & independent mechanisms
Are there non disjunction susceptibility gene(s)?- Mouse/Human/Pig/Other mammals
Checkpoint proteins on kinetochores

Question 7

Discuss the complex arrangement of spindle checkpoints in meiosis?

Answer 7

Complex arrangement of spindle checkpoint proteins in mammalian meiosis; signal transduction through on and off switch mechanisms; MAD2 is the key protein in this pathway; in humans MAPK is probably most relevant?

Question 8

Discuss paternal nondisjunction>

Answer 8

3-4% sperm are aneuploid
Chromosome specific
Age related nondisjunction?
Weak link
Contradictory
Achiasmate XY nondisjunction using FISH studies suggests that there is a paternal age effect

Question 9

Conseuence of aneuploidy?

Answer 9

Subfertility- aneuploid embryos have a lower implantation rate THAN euploid embryos
Early miscarriage- ~1/2 miscarriages are aneuploid (most- monosomic or trisomic)
Malformations- Leading genetic cause of multiple malformations, developmental disabilities and mental retardation in the pregnancies that survive to term

Question 10

Clinical feature of aneuploidy?

Question 11

Effect of mosaic aneuploidy?

Question 12

Common aneuploidy syndrome?

Question 13

sex aneuploidy syndrome?

Answer 13

SEX CHROMOSOMAL
Turner 45,-X 1 in 1000
Klinefelter’s 47,XY,+X 1 in 1000
Triple X 47,XX,+X 1 in 1000
Others 48,XY,+XX ; 49,XY,+XXX

Question 14

xxx females personality?

Answer 14

Tall and skinny

Learning problems and shy

may present with ovarian filure and infertility problems

Question 15

symptoms of klinfelters?

Answer 15

Question 16

xyy males?

Answer 16

learning and behacioural difficulties - ADHD or even ASD

large build ,heavy jaw, and big limbs.hands

impulsive behaviour, often violnt nature

Question 17

why do you get recurrent aneuploidy?

Answer 17

Age-related
Unknown meiosis 1 factors ?spindle proteins
Gonadal mosaicism?

Question 18

Prenatal screening?

Answer 18

First trimester ultrasound examination <12 weeks- increased nuchal thickness
Maternal serum markers
Selective prenatal diagnosis
- over 35 years of age
- previous aneuploidy
- high risk on screening
- abnormal ultrasound examination

Question 19

why would you give pre-implantation screening?

Answer 19

No genetic disease
Usually history of recurrent early miscarriages
Possibly useful in women over 35 years
Selective embryo transfer after single cell FISH for the three common aneuploidies- 21,18 and 13
?? Improved pregnancy rates

Question 20

Microdeletions?

Answer 20

In most children these are de novo
Recurrence risk is usually small ~ 1%
Higher recurrence
* Parental balanced chromosome rearrangement / inversion
* Gonadal mosaicism
Variable clinical picture
Contiguous gene syndromes

Question 21

Microduplications?

Answer 21

Presumed to have arisen de novo
Recurrence risk of ~1%
Gonadal mosaicism
Imprinting may have to be taken into consideration (e.g. dup14q23.4)
May indicate parental pericentric inversion
Examples include
Dup14q23.4- autism, developmental delay
Dup15q26- overgrowth, learning difficulties

Question 22

origins of microdelections/duplications?

Answer 22

Reciprocal autosomal rearrangement
X;autosome translocation
Paracentric inversion
Pericentric inversion

Question 23

Microduplication and delection syndromes?

Answer 23

del 2q37 (2)

Wolf Hirsohhorn (4)

Oru du chat (5)

Williams (7)

Langer Galdon (8)

Jacobsen (11)

WAGR (11)

Rb(13)

PW8/A8 (15)

Rubinstein - Taybi (16)

Miller-Muwaker (17)

Smith Magence (17)

CMT & HTSN (17)

18p (18)

18q (18)

Alagille (20)

del 22q11 (22)

del22q13 (22)

While O’ West Laughed Whilst Jacob-Sen Ran Past Rubbing His Cock & Holding Mary smitths Arm

Question 24

Ring Chromosomes?

Answer 24

Rare
99% arise as de novo sporadic events
Usually have phenotypic effect (usually picked up because of a dysmorphic developmentally delayed child / individual)
However – exceptions exist
Mild MR
Short stature
Mild dysmorphism
REMEMBER - Mosaicism

Question 25

Ring Xp symptoms?

Answer 25

Short Stature Turner Like Phenotype Moderate to severe learning difficulties Possibly other physical anomalies

Question 26

origin of microdeletions/duplications?

Answer 26

Most important underlying mechanism involves ‘non-allelic homolgous recombination between low-number copy repeats. This may result in depetions, duplications, inversions or complex rearrangements in some situations.

Question 27

William Beuren Syndrome symptoms?

Answer 27

* facial features * elastin arteriopathy (SVAS) * connective tissue weakness * mild mental retardation * behavioural profile * cognitive profile Looks like Tom Ashdown

Question 28

genetic of william beuren syndrome?

Answer 28

Another microdeletion contiguous gene syndrome in the same group is WBS. Typical case would present with characterisitic facies, SVAS, behavioural pattern- cocktail persolaity. The disorder is associated with a 1.5 Mb microdeletion at 7q11.23 segment. Several genes are present within this segment- Elastin being the major. The deleted segment is flanked by LCRS.

Question 29

Genes that are affected by WBS deletion?

Answer 29

7q11.23 segment contains several important genes- thus accounting for variable phenotype. ## Footnote FK-506 binding protein 36 - immunophilin, testis, heart, muscle, liver, kidney Frizzled 3 - WNT receptor, one of many in mammals Deleted in WS 3 - thought to be a transcriptional regulator BCL7B - member of family of genes. BCL7A originally cloned as part of a three-way translocation in Burkitts lymphoma. Unknown function. Syntaxin 1A - member of syntaxin family, expressed mainly in neurons Clostridium perfringens enterotoxin receptors 1 and 2 expressed in internal organs during development Elastin - structural component of elastic tissue LIM kinase 1 - LIM domain containing protein Williams-Beuren syndrome critical region 1 - RNA binding protein Replication factor C subunit 2 Cytoplasmic linker protein - molecular weight 115 kDa Williams-Beuren syncrome critical region 11 General transcription factor 2 I

Question 30

BEckwtih Wiedemann symptoms?

Answer 30

Large baby at birth Neonatal hypoglycemia Large tongue Umbilical hernia High risk for Wilms’ 11pdup in small# ?1% Variab0le phenotype: Imprinting of paternal alleles Looks like Lloyd

Question 31

15q11-13 deletions?

Answer 31

Prader-Willi syndrome \*neonatal hypotonia-floppy baby \*feeding problems-overeating/binge \*developmental dealy Angelman syndrome \*Happy looking \*No speech \*Epilepsy \*Severe developmental delay

Question 32

Prader willi syndrome Symptoms?

Answer 32

Facial profile Neonatal hypotonia Feeding problems Overweight Developmental delay Behavioural problems 15q12 del (Pat) Maternal UPD15

Question 33

Genetics of angelman syndrome?

Question 34

effect of 15q11-13 duplication?

Answer 34

Mild to moderate learning difficulties Autistic behaviour pattern-’pervasive development disorder’.. Asperger’s 1-2% of the genetic causes of Autism No specific clinical features Exclude cytogenetic distinction for euchromatic variant at 15q11.2-q13 ## Footnote

Question 35

Syndrome for microdeletion of 17p11.12

Answer 35

A well characterized dysmorphic syndrome associated with 17p11.2 microdeletion. This is proximal to CMT1A. Features include dysmorphic facies, multiple anomalies, and characteristic neuro-developmental and behavioural abnormalities

Question 36

Smith Magenis Syndrome genetics?

Answer 36

17p11 microdeletion syndrome Mild facial dysmorphic features Communication problems Learning difficulties Behaviour problems- self harm ? Lack or poor pain perception

Question 37

SMS Rep and SMS deletions?

Answer 37

Both CMT1A and SMS share common pathogenesis- presence of LCRs flanking the putative genes, called CMT1A-Rep and SMS-Rep. Unequal meiotic recombination results in either duplication (CMT1A) or microdeletion (SMS/HNPP). SMS has recently been associated with point mutations in the RAI1 gene, located within the dleted 17p11.2 segment. This gene codes for one of the Retinoic acid associated protein.

Question 38

22q11 deletion syndrome?

Answer 38

Congenital heart defect - interrupted aortic arch type B, persistence of the truncus arteriosus, tetralogy of Fallot ## Footnote Thyroid/Parathyroid abnormalities - hypoplastic or aplastic thymus gland and parathyroid gland Psychiatric illness - schizophrenia, bipolar disorder Facial dysmorphism Growth retardation

Question 39

22q11 deletion?

Answer 39

35 genes there No single region of overlap (SRO) No correlation between site/size of deletion and severity of clinical phenotype

Question 40

Yq deletion and male infertility?

Question 41

AZF regions?

Answer 41

Microdeletions of 3.5 MB in Yq12 Flanked by 229kb repeats Microdeletions of AZF regions • \< 4% in severe oligospermia • \< 18% in azoospermia • geno-phenotype correlations • de novo deletions of AZFc: 1/ 4,000 men

Question 42

What is array comparative geneomic hybridisation?

Answer 42

A new genome-based technique Uses array of known genomic sequences Compares patient’s whole genome Any loss of gain at specific genomic location can be precisely determined High sensitivity compared to FISH technique Fast becoming a first choice method followed by conventional/FISH cytogenetic methods