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Introduction

  • Most genes in the human genome are active. For more than 40 different regions in the genome, however, these are subject to imprinting, leading to mono-allelic, parent-specific gene expression.
  • These are clustered in groups at imprinted loci.
  • The patterns of gene expression are orchestrated by imprinting centres.
  • Methylation is a key mechanism in imprinting: when a gene is methylated, it is usually switched off. Imprinted genes therefore demonstrate differential DNA methylation of the maternally inherited and paternally inherited alleles, and are referred to as differentially methylated regions (DMRs).
  • During the development of the parental gametes, the methylation patterns characteristic of imprinted genes are erased and reset for transmission to offspring.
  • Many of the imprinted genes are involved in the regulation of pre- and postnatal growth.
  • Structural congenital anomalies are relatively rare features of imprinting conditions.

Mechanisms of disruption to imprinting patterns

The disruption of the parental-origin specific pattern of expression can occur through a variety of mechanisms, including:

  1. pathogenic variant in an expressed imprinted gene;
  2. deletion or duplication or an imprinted gene (involving a single gene or several within a larger copy number variant);
  3. uniparental disomy (UPD) (where both chromosome homologues – and therefore the genes within – are inherited from a single parent); or
  4. imprinting centre error (causing mis-expression of neighbouring imprinted genes).

Testing for imprinting disruption

If an imprinted syndrome is suspected clinically, it is important to use methylation testing of the imprinting control region (ICR) as the initial screening test. In healthy individuals, one copy of the ICR will be methylated, and the other unmethylated. Therefore, the average methylation level will be ~50%. A uniparental disomy or genetic deletion or duplication that affects the ICR will result in methylation levels of either 0% or 100%. This is also the case if the epigenetic state at one copy of the ICR is incorrect (an epigenotype-switch at the ICR).

Further tests will be required to identify the specific mechanism, which is important as it may inform the recurrence risk. Refer to Knowledge Hub resources for individual imprinting conditions, linked to in the table below, for further information on the typical mechanisms of disease and testing modalities employed.

Imprinting syndromes

A number of syndromes, caused by the disruption of the normal imprint, are outlined in the table below.

Chromosome region Gene Allele that is normally expressed Syndrome Clinical features
6 6q24.2 ZAC/PLAG1 Paternal Transient neonatal diabetes (occurs when there are two active copies of the gene) Poor growth/diabetes 1st week life. Remission 3-12 months. Non-insulin dependent diabetes in later life
7 7p21 GRB10 Maternal Silver-Russell syndrome (occurs when there are two active copies of the gene) Intrauterine growth restriction with near normal occipitofrontal circumference; asymmetry, frontal bossing, short stature, feeding issues, normal IQ
7q21.3 SGCE Paternal Myoclonic dystonia (occurs when there is a pathogenic variant in the paternal copy of the gene) Movement condition with myoclonic jerks and dystonic posturing with onset typically less than 18 years
7q32.2 PEG1/MEST Paternal Silver-Russell syndrome (occurs when there are no active copies of the gene) As above
11 11p15.5 H19 Maternal Silver-Russell syndrome and Beckwith-Wiedemann syndrome SRS: as above

BWS: prenatal overgrowth, macroglossia, exomphalos, lateralised overgrowth and a predisposition to embryonal tumours (particularly Wilms tumour)

11p15.5 IGF2 Paternal
11p15.5 CDKN1C Maternal Beckwith-Wiedemann syndrome (occurs when there are no functional copies of the gene) As above
14 14q32 DLK1 Paternal UPD = uniparental disomy

Paternal UPD14, or Wang syndrome (occurs when there are two active copies of the gene)

Paternal UPD14: distinctive facial appearance, bell-shaped thorax with ‘coat-hanger’ ribs, abdominal wall defects, developmental delay, polyhydramnios, placentomegaly
14q32 RTL1 Paternal
14q32 MEG3 Maternal Maternal UPD14, or Temple syndrome (occurs when there are two active copies of the gene) Maternal UPD14: pre- and postnatal growth retardation, hypotonia, precocious puberty, variable developmental delay, mild facial dysmorphism, small hands and feet
15 15q11-q13 SNRPN Paternal Prader-Willi syndrome (occurs when there are no active copies of the gene) Neonatal central hypotonic and poor feeding, childhood insatiable appetite and truncal obesity, short, small hands/feet/male genitalia, developmental delay
15q11-q13 UBE3A Maternal Angelman syndrome (occurs when there are no active copies of the gene) Severe delay, usually no speech, ataxic gait, microcephaly, excitable personality, seizures
20 20q13.32 GNAS Maternal Pseudo-hypoparathyroidism type 1B (PHP1B) (occurs when there are no active copies of the gene) Hypocalcemia, hyperphosphatemia, and increased serum PTH. May have features of Albright hereditary osteodystrophy (short 4th/5th metacarpals, short stature, obesity

Resources

For clinicians

References:

Tagged: Imprinting condition

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  • Last reviewed: 11/02/2022
  • Next review due: 11/02/2023
  • Authors: Dr Ellie Hay, Dr Elizabeth Radford
  • Reviewers: Dr Amy Frost, Professor Kate Tatton-Brown