Genetics of Learning disorders

Question 1

Turnaround time for microarray analysis?

Answer 1

28 days (although babies <1 year treated as urgent, aim for 14 day turnaround)

Question 2

IQ of less than what is defined as learning disability?

Answer 2

70

Question 3

Name of database with over 4000 syndromes?

Answer 3

Winter-Baraister Dysmorphology Database

Question 4

Main risk factor for trisomy disorders?

Answer 4

Increasing maternal age

Question 5

Causes of trisomy 21? (3)

Answer 5

Majority- non-disjunction
4% translocation
1% mosaic

Question 6

Recurrence risk if parent is a carrier of a 21/21 translocation?

Answer 6

100%

Question 7

Features of Edward syndrome (4)

Answer 7

Rockerbottom feet
Microcephaly
Hypertelorism
Clenched hands

Question 8

Features of Patau syndrome? (4)

Answer 8

Mental retardation
Scalp defect
Holoprosencephaly
Polydactyly

Question 9

Examples of microdeletion syndromes? (4)

Answer 9

PWS/AS
Williams syndrome
Smith-Magenis syndrome
Di George syndrome

Question 10

Examples of macrodeletion syndromes?

Answer 10

Cri-du-chat (terminal deletion of 5p)
Wolf-Hirshhorn (terminal deletion of 5p)
Miller-Dieker (terminal deletion 17p)
Smith Magenis (interstitial deletion 17p)

Question 11

Which is tolerated better, gain or loss of chromosomal material?

Answer 11

Gain

Question 12

Which are the commonest autosomal trisomies which seen in pregnancy loss?

Answer 12

16, 21, 22

Question 13

Of the trisomies which are viable only in mosaic form, which are the commonest?

Answer 13

8 and 9

Question 14

Where is mosaicism likely to originate from?

Answer 14

Post-zygotic non-disjunction during mitosis

Question 15

What other way can extra chromosomal material be present in a patient with learning difficulties?

Answer 15

Supernumerary abnormal chromosomes e.g. marker chromosomes if the chromosome origin unknown

Question 16

What is a ring chromosome?

Answer 16

Formed from a single chromosome, has the centromere intact but has loss of material from, and then fusion between, the p and q arms

Question 17

What are the two categories of ring chromosome?

Answer 17

Large- very little deleted, will normally be present in place of the normal chromosome e.g. 46, XX r(4)

Small ring chromosomes which are often present as an additional ring chromosome

Question 18

How can “dynamic mosacism” result from ring chromosomes?

Answer 18

Ring chromosomes are unstable at mitosis

Question 19

Techniques for detecting chromosomal abnormalities

Answer 19

G-band
FISH
Array CGH

Question 20

Resolution of a) G band b) FISH

Answer 20

a) 3-5 Mb

b) around 100Kb

Question 21

Drawbacks of array CGH?

Answer 21

Requires high quality DNA
Detects only genetic imabalance
Will not always detect mosaicism
Cannot detect triploidy
Provides no positional information (contrast to FISH)

Question 22

What technique/array is required to detect imprinting defects?

Answer 22

a SNP array

Question 23

Proportion of human genome made up by copy number variants?

Answer 23

12%

Question 24

If both parents have a normal karyotype but have recurrent pregnancies with the same deletion what can be assumed?

Answer 24

One of the parents is germline mosaic for the deletion

Question 25

Why is the risk for an insertion carrier generally higher than risk for a translocation carrier?

Answer 25

Because the unbalanced form consists of either gain or loss and not a combination of both

Question 26

What does the interpretation of a missense variant depend on?

Answer 26

The effect of the change on protein structure and function

Question 27

How can synonymous changes manifest clinically?

Answer 27

Create splice site, disrupt exon/splice enhancer or silencer sequences