Session 3 Summary cards

Question 1

Disorders that show anticipation.

Answer 1

1. HD
2. FraX
3. DM1
4. Dentatorubro-pallidoluysian atrophy
5. SCA1
6. SCA3
7. SCA7

Question 2

Examples of age related mosaicism. Cause.

Answer 2

Failure in DNA repair mechanism evidenced by NF2
Classic and mosaic forms are germline and have a higher frequency of frameshift mutations that somatic form - sporadic vestibular schwannoma.

Other examples: cancer, loss/gain of sex chromosomes with age.

Question 3

Example of mutation with reduced penetrance

Answer 3

c.907_909 del, Glu303del in TOR1A causing early onset primary dystonia.

30% penetrance. OK if not symptoms by 28

Question 4

Example of condition with reduced penetrance

Answer 4

Breast cancer due to BRCA1 mutation. 80% lifetime risk

Question 5

Examples of sex-limiting genes.

Answer 5

LHCGR (2p16.3) precocious male puberty. Constiutive activation of LH receptor (hypermorph)

Blepharophimosis, ptosis and epicathis inverusus (BPES) Type 1 (3q22.3) FOLXL2 polyalanine expansion. Predominantly expressed in ovaries resulting in POI

Question 6

Example of epistasis

Answer 6

Bombay phenotype.

Can lead to locus heterogenity. Same phenotype resulting from multiple genes, usually in same pathway.

Question 7

Example of pleiotropy.

Answer 7

PKU

Phe –> Tyr –> Melanin

Increased Phe = PKU
Reduced Tyr = reduced melanin = albinism

Question 8

Gene associated with XLD hypophosphatemia

Answer 8

PHEX (Xq22.1)

stimulates FGFR23 expression in bone and normal bone dev.

FGF23 inhibits phosphate reabsorption in kidney required for normal bone formation.

PHEX mutation leads to increase in FGF23 overactivity or means FGF23 is not broken down properly

Question 9

Examples of XLD conditions, gene, locus

Answer 9

1. XLD hypophosphataemia (PHEX, Xq22.1)
2. Alport Syndrome (COL4A5, Xq22.3)
3. Fragile X (FMR1, Xq27.3)

Question 10

Examples of XLD conditions with male lethality gene, locus

Answer 10

1. Intercontinentia pigmentia (IKBKG, Xq28)
2. Rett syndrome (MECP2, Xq28, CDKL5, Xp22.5) FOXG1 causes congenital/earlier onset form at 14q12
3. Oral-facial-digital syndrome 1 (OFD1 Xp22,2)

Question 11

Example of XLD where males unaffected

Answer 11

Craniofrontonasal syndrome caused by mutations in ephrin gene (EFNB1, Xq13.1)

Question 12

What makes the terms X-linked dominant/recessive difficult to use in practise? 5

Answer 12

1. Does not capture variable expressivity of x-linked disorders
   2) Does not take into account the multiple mechanisms that can result in disease expression in females

Question 13

XLR disorders, gene, locus

Answer 13

1. DMD/BMD/DMD-assiocated cardiomyopathy (dystrophin Xp21.1-2)

Question 14

Causes of females affected with XLR

Answer 14

1. XO
2. Del of other allele
3. Translocation/rearrangement disrupting XIC
4. UPD
5. Somatic mosaic
6. Skewing

Question 15

Mutation spectrum of DMD/BMD

Answer 15

Del/dup of 1 or more exons account for
65-70% of DMD
80-85% of BMD

Two hotspots:

1) 80% of dels in 44-53
2) 20% of dels in exons 2-20 (5’)

Duplication freqs are opposite

Question 16

XLR disorders and proposed gene therapy treatments.

Answer 16

1. DMD -
   stop codon readthrough applicable to 15% patients
   exon skipping therapy applicable to ~80% of DMD
2. Haemophilia A/B: IV adeno-associated viral vectors expressing Factor 8 or 9

Question 17

AR disorder and proposed gene therapy treatments.

Answer 17

SMA:
1) 18mer ASO010-27 (ISIS-SMN) in phase III trials for SMA infant - splicing modifier
2) scAAV9 carrying WT SMN gene. AveXis in phase I trials.
Potential microRNA biomarkers for treatment monitoring via blood test

Question 18

Examples of single gene haploinsufficient disorders, gene, locus

Answer 18

1. Familial hyerptrophic cardiomyopathy/HCM
   - MYH7 (14q11.2)
   - TNNT2 (1q32.1)
   - TNNT3 (11p15.5)
2. Dilated cardiomypathy - LMNA
3. Alagille syndrome
   - JAG1 (20p12.2)
   - NOTCH2 (1p12)
4. Aniridia (11p13)
5. GLUT1 deficiency syndrome (1p34.2)
6. HNPP (PMP22, 17p12)