Cytogenetic Disorders

Question 1

What is the liveborn incidence with 22q11.2 micro deletions?

Answer 1

1/4000

Question 2

What is the liveborn incidence with 22q11.2 micro duplication?

Answer 2

Much rarer than 22q11.2 micro deletions.

Question 3

What is CAT-EYE syndrome?

Answer 3

4 copies of 22q11.2 locus.

Question 4

What is the birth incidence of Crime du Chat?

Answer 4

1/15,000 live births

Question 5

What is the cytogenetic locus responsible for Cri du Chat?

Answer 5

5p DELETION. -> 5p15 is the critical region for Cri du Chat

Question 6

What are the facial features of Cri du Chat?

Answer 6

Microcephaly Hypertelorism Epicanthal folds Low set ears Micro/retrognathia

Question 7

What syndrome and molecular variant does this baby have?

Answer 7

CRI DU CHAT

5p-

Due to loss of 5p15 critical region. Note hypertelorism, epicanthal folds and microcephaly. Retrognathia also common.

Question 8

What parental allele is lost in Prader Wili?

Answer 8

Loss of paternal allele.

Remember because Prader Wili starts with a P for paternal

Question 9

What is the mnemonic for Prader Wili allele loss?

Answer 9

P in Prader Wili is for loss of PATERNAL allele expression

Question 10

What parental allele is lost in Angelman syndrome?

Answer 10

The Maternal allele is lost in Angelman.

Remember because these kids are sweet and a mother would love to have them

Question 11

What is the cytogenetic cause of XYY syndrome?

Answer 11

XYY syndrome can ONLY be caused by PATERNAL meisosis II nondisjunction.

Question 12

When do female cells engage X-inactivation?

Answer 12

Female cells inactivate one of the X chromosomes at RANDOM very early in development (before implantation).

Question 13

What is the 90 percentile range for normal female X-inactivation skewing?

Answer 13

Normal is 50% of cells have X-inactivated one parents X-chr in a woman.

90% of women will have X-inactivation ratios of 1/4 to 3/4.

IE this means 25%-75% of her cells are skewed. Less than 10% of women have X-skewing where greater than 75% one way or the other.

Question 14

What are the three situations where X-inactivation is NOT random

Answer 14

1) Structurally abnormal X -> The abnormal X is inactivated.
2) Balanced X;autosome: The normal X is inactivated
3) Unbalanced X;autosome: The abnormal X is inactivated

Question 15

What is the general rule for non-random X-inactivation?

Answer 15

Maintain gene dosage, so shut down what X chr that will keep things normal.

Question 16

What are the incidence of 47,XXY?

Answer 16

Klinefelters Disorder affects 1/600 males

Question 17

What is the clinical features of 47,XXY

Answer 17

Tall male with gonadal hypoplasia and slim shoulders. Often with gynecomastia (male breast development).

Question 18

What is the IQ impact of 47,XXY

Answer 18

Can have normal IQ (we’ve met one) but also possible for verbal IQ to low

Question 19

What is the behavorial impact of 47, XXY?

Answer 19

Klinefelters have no major behavorial deficits

Question 20

What is the impact of 47,XXY on fertility?

Answer 20

Infertile male (often first clinically observed for infertility workup).

Azoospermia and hypogonadism.

Question 21

What is the incidence of 47,XYY

Answer 21

1/1000 male births

Question 22

What is the clinical presentation of 47,XYY?

Answer 22

Tall but otherwise normal male appearance

Question 23

What is the IQ impact of 47,XYY?

Answer 23

Reduced verbal IQ, language and reading difficulties

Question 24

What is the behavioral impact of 47,XYY?

Answer 24

A subset of these patients will have behavioral problems (likely affiliated with lower IQ).

Question 25

What is the incidence of 47,XXX (Trisomy X)

Answer 25

1/1000 female births will have Trisomy X

Question 26

What is the clinical presentation of Trisomy X?

Answer 26

Hypotonia with delayed developmental milestones. Taller than normal. Learn+Language issues

Question 27

What is the IQ of Trisomy X?

Answer 27

Normal to low

Question 28

Behavioral impact of 47,XXX

Answer 28

Typically normal

Question 29

What is the fertility of Trisomy X?

Answer 29

Reduced fertility in some. Premature ovarian failure in some (ovaries fail before 40).

Question 30

What is the impact of variant Klinefelters?

Answer 30

More than one X. Any X beyong 47,XXY leads to more severe phenotype prediction.

Question 31

What is the impact of variant Trisomy X?

Answer 31

Additional X chromosomes will result in a more severe phenotype

Question 32

What is the incidence 45,X?

Answer 32

Turner syndrome occurs in 1/2500-1/4000 female births.

Question 33

What is the spontaneous abortion rate of 45,X fetuses?

Answer 33

99% of all 45,X (Turner) fetuses will abort spontaneously.

Question 34

What is the common clinical presentation of Turners syndrome?

Answer 34

Short

Webbed neck

Lymphedmia

Risk for cardiac abnormalities

Question 35

What is the diagnosis and molecular cause of this patients disorder?

Answer 35

45,X Turner syndrome.

Note webbed neck with short stature. This child is a survivor. 99% of other babies with this genotype will spontaneously abort.

Question 36

What does DSD stand for?

Answer 36

Disorder of sexual development

Question 37

What is gonadal dysgenesis?

Answer 37

Progressive loss of the germ cells followed by failure to correctly develop 2’ sexual characteristics.

Question 38

What is the molecular yield of chromosomal microarray testing in patients with intellectual disability?

Answer 38

Up to a 12-15% of intellectual disability patients have a pathogenic CNV detectable by chromosomal microarray.