Triplets

Question 1

Triplets diseases with expansions in coding region?

Answer 1

HD
SCA
SBMA

Question 2

Triplets disease with repeats in non-coding regions?

Answer 2

DM1 (CTG in 3’UTR)
Frax (CGG in 5’Utr)
Friedreich ataxia (GAA intrinsic)

Question 3

Key features of FRDA - gene, expansion, carrier drew & ranges

Answer 3

FXN (frataxin)
Carrier freq - 1:60- 1:100
GAA repeat intron 1
Normal 5-33
Premutation 34-65
Borderline 44-66
Fm 66-1700

Question 4

Evidence that repeat expansion produces gain of function response?

Answer 4

No other mutation found in gene
Expanded allele is transcribed and translated
Critical threshold
Anticipation - earlier onset with larger repeat size
Homozygotes identical to heterozygotes
Patients will deletion don’t manifest symptom

Question 5

Examples of polyalanine repeat disorders?

Answer 5

OPMD (PABPN1)
Holonprosencephaly (ZIC2)
X-linked Mr (ARX)
Synpolydactyly type 2 (HOXD13)
Hand foot genital syndrome (HOXA13)
Bpes (FOXL2)
X-linked hypopituitirism (SOX3)
Cleidicranial dysplasia (RUNX2)
Congenital central hypoventilation (PHOXB2)

Question 6

Features of polyalanine repeat disorders that differ from polyglutamine?

Answer 6

Imperfect pairing - GCU, GCC, GCA, GCG

Much smaller than CAG repeats
Don’t get anticipation
Meiotically and mitotically stable
Mostly TF
Mechanism likely crossing over between mispaired normal repeats
Frequently found as De novo