Imprinting disorders

Question 1

What is BWS?

Answer 1

Beckwith-Wiedemann syndrome

Question 2

Which region of the genome causes BWS? (2)

Answer 2

• Complex locus at 11p15.5 containing IGF2 and H19
• IGF2 is maternally imprinted so paternally expressed, H19 is paternally imprinted so maternally expressed

Question 3

What are the features of BWS? (3)

Answer 3

• Paediatric overgrowth disorder involving a predisposition to tumour development
• Variable clinical presentation but commonly large tongue and gigantism
• Most individuals are normal size by adulthood

Question 4

What are some of the causes of BWS? (3)

Answer 4

• Uniparental disomy (UPD) of paternal chromosome 11
• Duplication of paternal 11p15.5 region
• Hypomethylation of the imprinting control region of paternal 11p15.5

Question 5

What are examples of imprinting disorders in humans? (3)

Answer 5

• Beckwith-Wiedemann syndrome (BWS)
• Prader-Willi syndrome (PWS)
• Angelman syndrome

Question 6

What are the features of PWS? (3)

Answer 6

• Obesity
• Behaviour and cognitive issues
• Deficiencies in sexual development

Question 7

Which region of the genome causes PWS? (2)

Answer 7

• Loss of paternal 15q11-q13 region which is maternally imprinted meaning the maternal chromosome 15 can’t compensate for loss of paternal expression
• 70% cases caused by deletion of paternal 15q11-q13 and 25% cases caused by maternal UPD

Question 8

What are the features of Angelman syndrome? (4)

Answer 8

• Developmental deficiencies
• Sleep disorders
• Seizures
• Happy disposition

Question 9

Which region of the genome causes Angelman syndrome? (2)

Answer 9

• Loss of maternal 15q11-q13 specifically loss of the UBE3A gene which is paternally imprinted meaning the paternal chromosome 15 can’t compensate for loss of maternal expression
• 70% cases caused by deletion of maternal 15q11-q13, 10% caused by mutation of UBE3A and 3% paternal UPD

Question 10

What are the possible genetic mechanisms of PWS? (4)

Answer 10

• Deletion of the paternal PWS region 15q11-q13 (70% cases)
• Maternal UPD 15 (25% cases)
• Epigenetic or genetic mutations in the imprinting control region (ICR) of paternal 15 causing it to be wrongly silenced
• Translocations that separate the ICR from the PWS region

Question 11

What causes UPD?

Answer 11

Mitotic or meiotic non-disjunction events followed by trisomic rescue where 1 of the 3 copies of a chromosome is lost to become diploid again, sometimes resulting in 2 chromosomes being from the same parent

Question 12

Why do large translocations impact fertility?

Answer 12

Chromosomes struggle to pair up properly during meiosis

Question 13

What are possible treatments for PWS? (5)

Answer 13

• Currently no clinically approved gene therapy for PWS
• Reactivate the silenced genes on the maternal chromosome to compensate for the paternal deletion using epigenome editing with CRISPR and dCas9/CRISPR activation/downregulating the antisense transcript required for maintenance of silencing throughout development
• Introduce functional copies of the missing genes using viral vectors
• Tackling the symptoms
• Challenging because treatment depends on the mechanism by which you have PWS

Question 14

What is the challenge associated with gene therapy for congenital genetic disorders?

Answer 14

Impacts every cell in the body but can’t feasibly deliver a gene therapy appropriately to every cell

Question 15

What are the potential gene therapy strategies for PWS? (3)

Answer 15

• AAV-based gene therapy using AAV vectors to deliver functional copies of the missing genes to affected cells
• shRNA/AAV9 gene therapy which delivers shRNAs to silence expression of EHMT2, a chromatin remodeller which contributes to maternal PWS region silencing (also regulates lots of other genes)
• Targeting metabolic dysregulation (symptoms) by introducing genes such as BDNF into the hypothalamus to control appetite and control hyperphagia and obesity