Core diseases

Question 1

What type of disorder is Huntington disease?

Answer 1

Gain of function disorder

Huntington disease is characterized by an expansion of trinucleotide CAG repeats.

Question 2

What is the correlation between the number of CAG repeats and age of onset in Huntington disease?

Answer 2

Negative correlation; genetic anticipation occurs

The severity of the disease increases with successive generations while the age of onset decreases.

Question 3

What type of repeats are associated with fragile X syndrome?

Answer 3

CGG repeats

Question 4

What can cause repeat expansions in triplet repeat disorders?

Answer 4

Strand slipping during DNA replication

This occurs when DNA polymerase stutters while synthesizing repetitive sequences.

Question 5

What happens to proteins with expanded polyglutamine (polyQ) sequences?

Answer 5

They undergo conformational changes to form insoluble aggregates

These aggregates induce cellular proteotoxicity independent of the functions of their host proteins.

Question 6

What is the normal allele range for CAG repeats?

Answer 6

<26 repeats

Question 7

What is the repeat range for an intermediate (‘mutable normal’) allele?

Answer 7

27-35 repeats

Question 8

What is the repeat range for affected individuals in Huntington disease?

Answer 8

> 36 repeats

36-39 repeats show reduced penetrance; individuals with 40 or more show complete penetrance.

Question 9

What is the juvenile form of Huntington disease characterized by?

Answer 9

> 60 repeats

Question 10

What is the average age of onset for Huntington disease?

Answer 10

40 years

5-10% present with juvenile form (before age 20) and 25% present after age 50.

Question 11

Which type of transmission is associated with large expansions in Huntington disease?

Answer 11

Paternal transmission

This is attributed to the increased number of meiotic divisions in spermatogenesis.

Question 12

What testing can be offered to individuals with a 25% risk of Huntington disease whose parent does not want testing?

Answer 12

Exclusion test via haplotype analysis

This is used in prenatal testing.

Question 13

What are the two commonly used methods for sizing repeat expansions?

Answer 13

• Fluorescent polymerase chain reaction (PCR) sizing
• Repeat-primed PCR

Question 14

What does the fluorescent PCR sizing method involve?

Answer 14

Amplifying patient DNA with primers located on either side of the repeat region

One primer is fluorescently labelled, and capillary electrophoresis is used to separate PCR products.

Question 15

What is a key advantage of repeat-primed PCR?

Answer 15

Can amplify larger expansions

Question 16

What is a limitation of STR testing for large expansions?

Answer 16

Exact sizing may not be possible

Question 17

What is Spinocerebellar Ataxia (SCA)?

Answer 17

A group of neurodegenerative diseases affecting the cerebellum

Characterized by generalized in-coordination of gait, speech, and limb movements.

Question 18

What is the typical onset age for Spinocerebellar Ataxia?

Answer 18

Typically during adult life

Question 19

Which gene is associated with SCA7, known for particularly unstable CAG repeats?

Answer 19

ATXN7

Question 20

What is the clinical outcome of extreme anticipation in SCA7?

Answer 20

Children with early-onset, severe disease may die of complications before affected parent/grandparent is symptomatic

Question 21

What types of SCA are commonly tested?

Answer 21

• SCA types 1
• SCA types 2
• SCA types 3
• SCA types 6
• SCA types 7
• SCA types 17

Question 22

What chromosome region is affected in Beckwith-Wiedemann Syndrome (BWS)?

Answer 22

11p15

Question 23

What are the main molecular causes of BWS?

Answer 23

Hypomethylation of ICR2 (KvDMR) – 50–60%

Paternal uniparental disomy (UPD 11p15) – 20–25%

Hypermethylation of ICR1 (H19/IGF2) – 5–10%

CDKN1C mutations – ~5%

Duplications, deletions – 1–2%

Question 24

What is the first-line test for BWS diagnosis?

Answer 24

MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification).

Question 25

What are second-tier diagnostic tests for BWS?

Answer 25

SNP arrays for mosaicism Microsatellite testing if SNP is negative CDKN1C sequencing ICR1 sequencing

Question 26

What are common physical features of BWS?

Answer 26

Overgrowth (height/weight) Macroglossia Hemihypertrophy Neonatal hypoglycemia Wilms' tumor risk

Question 27

What are the two imprinting control regions (ICRs) in BWS?

Answer 27

ICR1 (telomeric, regulates IGF2/H19) and ICR2 (centromeric, regulates CDKN1C/KCNQ1OT1/KCNQ1)

Question 28

What is the function of CDKN1C?

Answer 28

A maternally expressed cyclin-dependent kinase inhibitor important for cell cycle control.

Question 29

Which genes are regulated by ICR1?

Answer 29

IGF2 (paternally expressed) and H19 (maternally expressed). The imprinting process ensures that only one copy of a gene is expressed, either from the paternal or maternal allele. In BWS, this process is disrupted, and the paternal IGF2 gene is expressed from both alleles, leading to IGF2 overexpression

Question 30

what is the function of H19 in IGF2 regulation?

Answer 30

H19 competes for IGF2 enhancers and blocks IGF2 expression on the maternal allele.

Question 31

what is the role of KCNQ1 in BWS?

Answer 31

maternally expressed potassium channel gene; biallelic in the heart. Mutations cause Long QT syndrome.

Question 32

What two chromosomal regions are commonly associated with Silver-Russell Syndrome (SRS)?

Answer 32

11p15.5 and chromosome 7.

Question 33

What is the significance of the 11p15.5 region in SRS?

Answer 33

contains a 1Mb cluster of imprinted genes involved in fetal and placental growth.

Question 34

What is the most common molecular abnormality in SRS?

Answer 34

Hypomethylation of H19/IGF2:IG-DMR (ICR1) at 11p15.5 (40–60%).

Question 35

What is the effect of paternal H19/IGF2 hypomethylation?

Answer 35

Loss of paternal IGF2 expression and gain of maternal H19 expression → growth restriction.

Question 36

What happens with maternal duplication of centromeric or both 11p15 domains?

Answer 36

rowth retardation due to increased dosage of CDKN1C.

Question 37

What are first-line tests for diagnosing SRS?

Answer 37

Methylation analysis at 11p15.5 and UPD7, microarray, and next-generation sequencing (NGS) panel.

Question 38

What are common management strategies for SRS?

Answer 38

Early feeding and nutrition support Multidisciplinary care and growth hormone therapy

Question 39

Summary of BWS

Answer 39

Normal development relies on a delicate balance of gene expression from both maternal and paternal copies of genes. In BWS, this balance is disrupted in the 11p15 region, where genes like IGF2 (paternally expressed, promoting growth) and CDKN1C (maternally expressed, suppressing growth) are imprinted Improper imprinting (one is active one is inactivated), often due to methylation changes, can lead to overgrowth and other BWS features. The CDKN1C gene is an imprinted gene, meaning its expression is regulated by the parental origin of the DNA. This means that only one copy of the gene (the maternal copy) is expressed, and a loss-of-function mutation in the active maternal copy leads to the overgrowth associated with BWS