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Chromosome Disorders Flashcards

1
Q

Ways of identifying genes?

A

G-Banding

PFGE & FISH

DNA sequencing

X-Ray Crystollography

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2
Q

What occurs in mosai form?

A

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

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3
Q

origin of aneuploidy?

A

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

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4
Q

Non-disjunction in aneuploidy?

A

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

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5
Q

discuss meiosis and spindle formation?

A

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

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6
Q

2 hit hypothesis of non-disjuncton?

A

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

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7
Q

Discuss the complex arrangement of spindle checkpoints in meiosis?

A

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?

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8
Q

Discuss paternal nondisjunction>

A

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

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9
Q

Conseuence of aneuploidy?

A

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

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10
Q

Clinical feature of aneuploidy?

A
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11
Q

Effect of mosaic aneuploidy?

A
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12
Q

Common aneuploidy syndrome?

A
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13
Q

sex aneuploidy syndrome?

A

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

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14
Q

xxx females personality?

A

Tall and skinny

Learning problems and shy

may present with ovarian filure and infertility problems

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15
Q

symptoms of klinfelters?

A
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16
Q

xyy males?

A

learning and behacioural difficulties - ADHD or even ASD

large build ,heavy jaw, and big limbs.hands

impulsive behaviour, often violnt nature

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17
Q

why do you get recurrent aneuploidy?

A

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

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18
Q

Prenatal screening?

A

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

19
Q

why would you give pre-implantation screening?

A

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

20
Q

Microdeletions?

A

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

21
Q

Microduplications?

A

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

22
Q

origins of microdelections/duplications?

A

Reciprocal autosomal rearrangement
X;autosome translocation
Paracentric inversion
Pericentric inversion

23
Q

Microduplication and delection syndromes?

A

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

24
Q

Ring Chromosomes?

A

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

25
Q

Ring Xp symptoms?

A

Short Stature

Turner Like Phenotype

Moderate to severe learning difficulties

Possibly other physical anomalies

26
Q

origin of microdeletions/duplications?

A

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.

27
Q

William Beuren Syndrome symptoms?

A
  • facial features
  • elastin arteriopathy (SVAS)
  • connective tissue weakness
  • mild mental retardation
  • behavioural profile
  • cognitive profile

Looks like Tom Ashdown

28
Q

genetic of william beuren syndrome?

A

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.

29
Q

Genes that are affected by WBS deletion?

A

7q11.23 segment contains several important genes- thus accounting for variable phenotype.

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

30
Q

BEckwtih Wiedemann symptoms?

A

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

31
Q

15q11-13 deletions?

A

Prader-Willi syndrome
*neonatal hypotonia-floppy baby
*feeding problems-overeating/binge
*developmental dealy

Angelman syndrome
*Happy looking
*No speech
*Epilepsy
*Severe developmental delay

32
Q

Prader willi syndrome Symptoms?

A

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

33
Q

Genetics of angelman syndrome?

A
34
Q

effect of 15q11-13 duplication?

A

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

35
Q

Syndrome for microdeletion of 17p11.12

A

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

36
Q

Smith Magenis Syndrome genetics?

A

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

37
Q

SMS Rep and SMS deletions?

A

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.

38
Q

22q11 deletion syndrome?

A

Congenital heart defect - interrupted aortic arch type B, persistence of the truncus arteriosus, tetralogy of Fallot

Thyroid/Parathyroid abnormalities - hypoplastic or aplastic thymus gland and parathyroid gland

Psychiatric illness - schizophrenia, bipolar disorder

Facial dysmorphism

Growth retardation

39
Q

22q11 deletion?

A

35 genes there

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

40
Q

Yq deletion and male infertility?

A
41
Q

AZF regions?

A

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

42
Q

What is array comparative geneomic hybridisation?

A

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

43
Q
A

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