18.03.10 Imprinted chromosomes and summary of syndrome Flashcards Preview

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Give a definition of imprinting.

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


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

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


Which mechanisms can lead to imprinting disorders?

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.


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

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


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

Typically involved in growth and development and metabolism

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


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

Prader-Willi syndrome
Angelman syndrome


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

Beckwith-Weidemann syndrome
Silver-Russell syndrome


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

Pseudohypoparathyroidism type b


Which imprinting disorders are associated with genes at 14q32?

Temple syndrome
Kagami-Ogata syndrome


Which imprinting disorders are associated with genes at 6q24?

Transient neonatal diabetes


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

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).


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

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


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

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

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


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

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


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

Incidence: 1 in 100,000

Clinically heterogeneous phenotype


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%)


What is the incidence and clinical features of PWS?

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)



Short stature

Small hands and feet


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

~70% (paternal) deletion

~ 30% matUPD

~2% Imprinting errors


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

~70% (maternal) deletion

~ 5% patUPD

~5% Imprinting errors

~10% UBE3A point mutations

~10% have no abnormality detected


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

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.


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

TNDM1 (70%)

Paternal allele expression as maternal promoter region methylated.


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

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%)


What is the incidence and clinical features of AS?

1 in 12-20,000

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

Severe mental retardation


Absent speech & inappropriate laughter

Microcephaly, wide open mouth, prominent chin & protruding tongue

Dev delay by 6 months




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

Pre and postnatal growth failure


Large head growth (30% cases)

Mild facial abnormalities

Central obesity developing with age

Small hands and feet

Early onset puberty (~8.7 years)


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

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


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

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).


What are the clinical features associated with GNAS mutations?

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


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

Maternal inheritance of such mutations leads to PHP-Ia

Paternal inheritance of the same mutations leads to PPHP


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

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