Trinucleotide Repeats

Question 1

__________ is when the gene is passed on from generation to generation the number of tandem repeats can increase (expands) leading to worsening abnormalities in gene expression and function: Earlier onset, worse phenotype

Answer 1

anticipation

Question 2

Tandem repeat gene disorders with maternal expansion

Answer 2

Myotonic dystrophy and Fragile X

Question 3

Tandem repeat gene disorder with paternal expansion

Answer 3

Huntington’s disease

Question 4

Mechanism of Fragile X and Friedereich Ataxia

Answer 4

Failure to transcribe/translate gene product

Question 5

Mechanism of Huntingtons, DRPLA, SCA and SBMA

Answer 5

Build up of aggregates

Question 6

Mechanism of myotonic dystrophy and fragile X tremor/ataxia syndrome (FXTAS)

Answer 6

Interference with neighboring genes (in transcription)

Question 7

First tandem repeat disorder discovered

Answer 7

Fragile X syndrome 1991

Question 8

1 cause of ataxia in adults

Answer 8

Friedreich ataxia

Question 9

1 cause of inherited moderate intellectual disability?

Answer 9

Fragile X
second only to trisomy 21

Question 10

Fragile X gene?

Answer 10

FMR1 - fragile X messenger ribonucleoprotein
FMR2

Question 11

Fragile X is caused by a _______________ repeat in the _____________ region of the ______________ gene and chromosome _______________

Answer 11

CGG
5 prime UTR
FMR1
Xq27F

Question 12

Friedreich ataxia is caused by a ________ trinucleotide repeat in the ___________ gene on chromosome ______________ and in the _____________ (exon/intron)

Answer 12

GAA
X25
9q13
intron

Question 13

Fragile X is observed after _____________ CGG repeats

Answer 13

> 230 CGG

Question 14

Friedreich ataxia is observed after ___________ GAA repeats

Answer 14

> 100 GAA

Question 15

Myotonic dystrophy is caused by a ____________ repeat in the _____________ gene on chromosome _____________ in the ___________ region

Answer 15

CTG
DMPK
19q13
3 prime UTR

Question 16

Myotonic dystrophy is observed after ___________ CTG repeats

Answer 16

50-thousands

Question 17

Huntington disease is caused by a ______________ repeat in the ____________ gene on chromosome __________________ in the ______________ (exon/intron)

Answer 17

CAG
HDD
4p16
exon

Question 18

Spinobulbar atrophy (Kennedy disease) is caused by a ________________repeat in the _____________gene on chromosome _____________________ in the ___________________ (exon/intron)

Answer 18

CAG
AR
Chromosome Xq13
exon

Question 18

Hungtington disease is observed after __________________ CAG repeats

Answer 18

36-121

Question 19

Spinobulbar atrophy is observed after __________________ CAG repeats

Answer 19

38-62

Question 20

Loss of frataxin leads to altered _____________ homeostasis and ____________ dysfunction

Answer 20

iron
mitochondrial

Question 21

Most tandem repeat disorders have ______________ __________________ inheritance

Answer 21

autosomal dominant

Question 22

SBMA (Kennedy syndrome) has _______ _____________ inheritance

Answer 22

X-linked

Question 23

Friedreich ataxia has _____________ _______________ inheritance

Answer 23

AR

Question 24

The most common mechanism underlying all tandem repeat disorders

Answer 24

slipped pairing

Question 25

FXTAS fragile x tremor ataxia syndrome is caused by ____________ to __________________ repeats of CGG

Answer 25

65-200

Question 26

Tandem repeats with long face, bossed forehead, ID, autism, large ears, flexible joints, macroorchidism, single palmar crease and flat feet

Answer 26

Fragile X syndrome

Question 27

Fragile X syndrome is due to __________________ of FMR1 while FXTAS is due to _____________________

Answer 27

Fragile X due to loss of expression of FMR1 - loss of dendritic pruning and altered signaling FXTAS - overproduction of FMR1 mRNA (reduced protein)

Question 28

FXTAS occurs in the ________________ of children with Fragile X and shows increased (2-5x) FMR1 mRNA production, decreased FMR1 protein production and cytoplasmic inclusions which label with _____________

Answer 28

grandfathers ubiquitin

Question 29

FMR1 expands in _______________ alleles

Answer 29

maternal

Question 30

In the 5 prime UTR of FMR1 on chromosome Xq27.3 the CGG repeats can be interrupted by ________ repeats at 9/10 or 19/20 which decreases CGG expansion

Answer 30

AGG Sequence of 33-39 CGG repeats after the AGG (uninterrupted) leads to instability of maternal

Question 31

How is Friedreich ataxia (FRDA) inherited and does it show anticipation?

Answer 31

AR - chromosome 9q13 No anticipation

Question 32

In addition to ataxia, FRDA causes lack of iron integration into ______________ and _____________ of spinal neurons as well as loss of PVT, diabetes and cardiomyopathy

Answer 32

mitochondria ferroptosis

Question 33

The FRDA ___________ expansion occurs where in the gene?

Answer 33

GAA (german ataxia ataxia) intron (Alu/SINE element)

Question 34

96% of FRDA have ______________ expansion alleles

Answer 34

homozygous

Question 35

Myotonic dystrophy is due to ____________ repeats in 3prime UTR of DMPK (DM1) and __________ repeats in DM2 (ZNF9)

Answer 35

CTG CCTG

Question 36

DM anticipation is through the __________________ (maternal/paternal)

Answer 36

maternal

Question 36

DM is a multisystem disorder, involving smooth and cardiac muscle wasting, the CNS and endocrine glands (pancreas=diabetes), and it causes __________ in the eyes, hypersomnia, premature balding and calcifying epithelioma (pilomatrixoma)

Answer 36

cataracts

Question 37

Myotonic dystrophy is associated with ______________ repeats of CTG

Answer 37

50-thousands

Question 37

FMR1 testing no 1 and no 2

Answer 37

1. microarray and FMR1 2. panel testing

Question 38

In myotonic dystrophy (DM) variant _____________ sequences interrupt the CTG repeat and stabilize anticipation

Answer 38

repeat CCG, CGT, CGG, CAG

Question 38

DMPK shows somatic ______________ and multiple possible mechanisms including RNA toxicity, altering expression neighboring genes and haploinsufficiency

Answer 38

mosaicism

Question 39

Myotonic dystrophy testing includes: _______________--

Answer 39

physical exam and history TP-PCR panels - but mosaic

Question 40

Polyglutamine (CAG tandem repeat disorders) show __________ ____________ inheritance and ______________ anticipation with a gain of function in huntingtin

Answer 40

autosomal dominant paternal anticipation

Question 41

Polyglutamine protein aggregates found in the _______________________

Answer 41

nucleus

Question 42

HDD is penetrant at greater than ____________ CAG repeats

Answer 42

36

Question 43

CAG repeats occur in the _____________ exon of HDD

Answer 43

First

Question 44

Two X-linked tandem repeat disorders

Answer 44

Fragile X SBMA

Question 45

In SBMA the CAG repeat occurs in the first ___________ (exon/intron) of the _________ gene

Answer 45

exon AR

Question 46

Tandem repeat disorder that affects the anterior horn, dorsal horn and bulbar region and may cause androgen insensitivity and gynecomastia

Answer 46

SBMA Kennedy syndrome

Question 47

Spinocerebellar ataxias are caused by __________ tandem repeats in genes such as SCA1, 2, 3 ....

Answer 47

CAG

Question 48

Inheritance pattern of ALS?

Answer 48

Autosomal dominant

Question 49

ALS is caused by a _____________ tandem repeat in the _____________ gene

Answer 49

hexanucleotide (GGGGCC) C9orf72 gene

Question 50

ALS phenotype (UMN, LMN and dementia) at ______________ repeats

Answer 50

>60