18.03.10 Imprinted chromosomes and summary of syndrome

Question 1

Give a definition of imprinting.

Answer 1

an epigenetic phenomenon that leads to parent-specific differential expression of a subset of mammalian genes

Question 2

Give a brief overview of imprinting, how it is established and maintained.

Answer 2

1. > 90 imprinted genes have been identified in humans and mice
2. Imprinting can be incomplete and/or tissue specific
3. Imprinted genes are usually present in clusters or imprinting domains, about 1MB in length, rich in CpG islands and contain both maternally and paternally expressed genes
4. Clusters are regulated by imprinting control regions (ICRs)
5. DNA methylation plays a crucial role in the establishment and maintenance of genomic imprinting
6. All ICRs identified so far are differentially methylated regions (DMRs) – DNA is methylated on one parental allele
7. Generally, patterns of DNA methylation in somatic cells are stable once established - transmitted from cell to cell during cell division
8. The imprinting marks must be reset during gametogenesis to reflect the sex of the parent for the next generation

Question 3

Which mechanisms can lead to imprinting disorders?

Answer 3

1. UPD: Both chromosomes in a cell are derived from a single parent (see notes 15.01.22). If the chromosome region contains an imprinted gene, UPD will be associated with alterations in gene expression.
2. Deletion: Loss of gene expression by deletion of an expressed gene on that allele, or deletion of the ICR leading to loss of regulatory control
3. Duplication: can double the expression of imprinted genes
4. Mutation on the active allele: associated with parent-of-origin effects on clinical phenotype.
5. Epimutation: Specific loss of methylation (hypomethylation) of gain of methylation (hypermethylation) at an ICR without any change in DNA sequence. Alters expression of imprinted gene.

Question 4

How many loci have been associated with imprinting disorders in humans? What are they?

Answer 4

6 loci:

1. 6q24
2. 11p15.5
3. 14q32
4. 15q11.2
5. 20q13.2

Question 5

What roles do imprinted genes usually have? What are the differences between the maternal and paternal genes?

Answer 5

Typically involved in growth and development and metabolism

Maternally imprinted genes associated with undergrowth
Paternally imprinted genes associated with overgrowth

Question 6

Which imprinting disorders are associated with genes at 15q11.2?

Answer 6

Prader-Willi syndrome

Angelman syndrome

Question 7

Which imprinting disorders are associated with genes at 11p15.5?

Answer 7

Beckwith-Weidemann syndrome

Silver-Russell syndrome

Question 8

Which imprinting disorders are associated with genes at 20q13.3?

Answer 8

Pseudohypoparathyroidism type b

Question 9

Which imprinting disorders are associated with genes at 14q32?

Answer 9

Temple syndrome

Kagami-Ogata syndrome

Question 10

Which imprinting disorders are associated with genes at 6q24?

Answer 10

Transient neonatal diabetes

Question 11

What is am example of a disease associated with global imprinting defects?

Answer 11

1. Familial biparental hydatidiform mole (FBHM)

Only known pure maternal-effect recessively inherited disorder in humans

Affected women (developmentally normal themselves) suffer repeated pregnancy loss because of the development of the conceptus into a complete hydatidiform mole in which extraembryonic trophoblastic tissue develops but the embryo itself suffers early demise.

Results from genome-wide failure to correctly specify or maintain a maternal epigenotype at imprinted loci.

The multilocus imprinting failure suggests that the genetic defect must be trans-acting. The autosomal recessive inheritance of FBHM is thus consistent with the idea that affected (homozygous mutant) mothers are deficient in a trans-acting gene product.

Studies of families in which HM segregates has led to the identification of NLRP7 and KHDC3L as 2 of the genes responsible. NLRP7 and KHDC3L may interact as components of an oocyte complex that is directly or indirectly requires determination of epigenetic status on the oocyte genome (Nguygen & Slim, 2014).

Question 12

Why have global imprinting defects been linked to ART? What are the possible selection biases introduced?

Answer 12

The timing of ART coincides with the establishment and maintenance of imprinting

It has been suggested that ovarian stimulation and culture medium for embryos can affect DNA methylation and expression of imprinted genes.

ART populations are different from naturally conceived populations: increased age, increased frequency of reproductive loss, low fertility, therefore link between ART and aberrant methylation remains unclear

Question 13

What is the incidence of BWS? What % of cases are sporadic?

Answer 13

Incidence: 1/13 700 live-births, equal frequency in males and females

85% sporadic
15% familial (AD; incomplete penetrance)

Question 14

Name the genes associated with BWS and whether they are maternally or paternally expressed?

Answer 14

GF2 paternally expressed (involved in regulation of embryonic growth and development)

H19 maternally expressed (tumour suppressor activity)

CDKN1C maternally expressed

KCNQ1 maternally expressed

KCNQ1OT1 paternally expressed

Question 15

What is the incidence of SRS? What are the different mechanisms that can lead to SRS?

Answer 15

Incidence: 1 in 100,000

Clinically heterogeneous phenotype

Etiology:

1. Maternal UPD7 - show a milder phenotype (5-10%)
2. Imprinting alteration at 11p15.5 (38-64%)
3. Submicroscopic chromosomal aberrations in chromosomes 7, 11, and 17 (1%)

Question 16

What is the incidence and clinical features of PWS?

Answer 16

1 in 15,000 births

Caused by loss of paternal contribution of

15q11-q13 (Maternal UPD)

Severe neonatal hypotonia & failure to thrive

Hyperphagia resulting in obesity (diabetes & cardiac failure)

Mild-moderate MR & behavioural disorders (stubborness, temper tantrums, poor peer interactions)

Hypopigmentation

Hypogonadism

Short stature

Small hands and feet

Question 17

What are the different aetiologies of PWS? What proportion of cases do they account for?

Answer 17

~70% (paternal) deletion

~ 30% matUPD

~2% Imprinting errors

Question 18

What are the different aetiologies of AS? What proportion of cases do they account for?

Answer 18

~70% (maternal) deletion

~ 5% patUPD

~5% Imprinting errors

~10% UBE3A point mutations

~10% have no abnormality detected

Question 19

What is the incidence and clinical features of transient neonatal diabetes?

Answer 19

1:200,000 - 1:400,000 live births

Neonatal diabetes: form of neonatal diabetes mellitus that presents soon after birth (usually first 6 months), undergoes spontaneous remission during infancy but may relapse to a permanent form of diabetes mellitus in childhood or adolescence. IUGR is often seen.

Question 20

What is the most common cause of TNDM? Which genes are associated with this condition? Which chromosome are the expressed from

Answer 20

TNDM1 (70%)

PLAG1
HYMA1
Paternal allele expression as maternal promoter region methylated.

Question 21

What are the different aetiologies of TNDM? What proportion of cases do they account for?

Answer 21

Paternal UPD6 (complete or segmental) (~40%)

Duplication of imprinted region at 6q24 region on paternal homologue (~32%)

Hypomethylation of maternal ZAC/HYMAI (resulting in expression of genes which are normally silenced) (~28%)

Question 22

What is the incidence and clinical features of AS?

Answer 22

1 in 12-20,000

Caused by loss of maternal contribution of 15q11-q13 (Paternal UPD)

Severe mental retardation

Ataxia

Absent speech & inappropriate laughter

Microcephaly, wide open mouth, prominent chin & protruding tongue

Dev delay by 6 months

Hypopigmentation

Seizures

Question 23

What are the features of Temple syndrome/ matUPD(14)?

Answer 23

Pre and postnatal growth failure

Hypotonia

Large head growth (30% cases)

Mild facial abnormalities

Central obesity developing with age

Small hands and feet

Early onset puberty (~8.7 years)

Question 24

What are the features of paternal UPD14 (aka Kagami-Ogata syndrome or Wang Syndrome)

Answer 24

More severe than matUPD(14)

Placentomegaly and polyhydramnios

Small bell-shaped thorax with coat hanger appearance of the ribs seen on US scan (this may be lethal or require long-term mechanical ventilation)

Abdominal wall defects

Facial abnormality

Question 25

What is GNAS? Which phenotypes can be associated with GNAS mutations?

Answer 25

GNAS (guanine nucleotide-binding protein, α stimulating) is a complex imprinted locus (20q13.11) that produces multiple transcripts by the use of alternative promoters and splicing. The most well characterised transcript is the α-stimulatory subunit of the G protein (expressed biallelically in nearly all tissues). Other transcripts are expressed exclusively from either the paternal or maternal GNAS allele.

Associated with:
Pseudohypoparathyroidism types Ia & Ib (PHP-Ia & Ib) and Pseudopseudohypoparathyroidism (PPHP).

Question 26

What are the clinical features associated with GNAS mutations?

Answer 26

Albright hereditary osteodystrophy (AHO), which includes short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation

PHP-Ia: AHO phenotype plus hormone resistance (PTH and TSH)

PPHP: AHO phenotype with no evidence of hormone resistance

PHP-1b: no AHO phenotype; renal resistance to PTH

Question 27

Heterozygous inactivating mutations within Gs-encoding GNAS exons are found in patients with PHP-Ia and in patients with PPHP:

Answer 27

Maternal inheritance of such mutations leads to PHP-Ia

Paternal inheritance of the same mutations leads to PPHP

Question 28

PHP Ib is caused by methylation and imprinting defects of the maternal GNAS gene

Answer 28

Results in loss of expression of the Gs-alpha protein in renal proximal tubules (only maternal allele expressed in these cells)

Deletions in the differentially methylated region (DMR) of the GNAS locus (loss of imprinting at the 5’ exon A/B DMR); typically associated with a 3-kb microdeletion that disrupts the neighbouring STX16 locus

deletions removing the entire NESP55 DMR, GNAS transcript, have also been identified in some PHP-Ib individuals who show loss of all maternal GNAS imprints