Genomic Imprinting — Prader-Willi, Angelman and Other Imprinting Disorders

Genomic imprinting is a process in which the expression of a gene depends on the parent who transmitted it. For an imprinted gene only one copy, maternal or paternal, is expressed; the other is silenced, usually by DNA methylation at imprinting control regions. The silencing mark is set in the germline, which is why the parental origin of a deletion or mutation changes the disease it causes.

The consequence is that the usual Mendelian rules fail. A deletion inherited from the father can cause one syndrome while the identical deletion inherited from the mother causes a different one, because the remaining copy is silenced. Prader-Willi syndrome was the first genetic disorder recognised to be caused by genomic imprinting.

Both syndromes map to the same imprinted region on the long arm of chromosome 15, 15q11.2-q13. The region contains genes expressed only from the paternal chromosome (the Prader-Willi region, including SNRPN) and the gene UBE3A, which is expressed from the maternal chromosome in neurons.

In neurons the paternal UBE3A allele is silenced by the UBE3A antisense transcript (UBE3A-ATS), a long non-coding RNA transcribed from the Prader-Willi imprinting centre. Neurons are therefore wholly dependent on the maternal UBE3A allele, so loss of the maternal allele removes UBE3A protein from neurons.

Prader-Willi syndrome (PWS) results from loss of expression of paternally inherited genes on 15q11.2-q13 and affects metabolic, endocrine and neurological systems. Prevalence is about 1 in 20,000 to 30,000 births, and it is the most common genetic cause of life-threatening obesity. Hypothalamic dysfunction underlies most features.

Diagnosis starts with DNA methylation analysis, which detects over 99 per cent of cases; follow-up testing shows whether the cause is a deletion (FISH), maternal disomy (chromosomal microarray) or an imprinting defect. Management is multidisciplinary: feeding support in infancy, strict control of food access once hyperphagia begins, vitamin and mineral supplements, physical and occupational therapy, and recombinant growth hormone from diagnosis, ideally before the first birthday. Orchidopexy is usually needed for cryptorchidism.

Angelman syndrome is a classic imprinting disorder caused by loss of function of the maternally inherited UBE3A gene on 15q11.2-q13. Harry Angelman described it in 1965; the old term "happy puppet syndrome" is now deprecated. Prevalence is about 1 in 12,000 to 20,000 live births.

• Development: severe developmental delay evident by 6 to 12 months; severe speech impairment, with up to 85 per cent essentially nonverbal.
• Gait: ataxic, wide-based gait with arms raised and flexed; about 10 per cent never walk independently.
• Behaviour: happy demeanour with easily provoked laughter, hand flapping, mouthing, short attention span and fascination with water.
• Seizures affect about 80 per cent by age 3; sleep disturbance affects 70 to 80 per cent; relative microcephaly develops by age 2.
• EEG abnormalities in 80 to 96 per cent; the most specific is high-amplitude frontal notched delta activity.
• Deletion cases often have hypopigmentation (the deletion includes OCA2) and lose GABRB3, a GABA receptor subunit gene implicated in seizure susceptibility.

Diagnosis follows a stepwise molecular algorithm. Step 1 is methylation analysis (MLPA), abnormal in about 80 per cent of cases, which confirms the diagnosis but not the mechanism. Step 2 is deletion testing by microarray, FISH or MLPA (about 70 per cent of cases are deletion-positive). Step 3 is paternal UPD testing, and then imprinting-centre analysis. Step 4 is UBE3A sequencing when methylation is normal but suspicion remains high, because UBE3A mutations have a normal methylation pattern. No disease-modifying therapy is currently approved; management is multidisciplinary, with seizure control a priority.

A syndrome can arise by deletion, by uniparental disomy (UPD), or by failure of the imprint itself. In UPD both copies of a chromosome come from one parent, typically through trisomy rescue or monosomy correction. The result is an imbalance of imprinted genes despite a normal chromosome count.

Rare familial PWS arises when a paternal imprinting-centre microdeletion is passed down, inherited from the paternal grandmother. Most PWS cases are sporadic.

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome and is a human imprinting disorder of chromosome 11p15, with hemihypertrophy, macrosomia, macroglossia and abdominal wall defects such as omphalocele. Two imprinting control regions, IC1 and IC2, regulate gene expression in this region. Embryonal tumours (Wilms tumour, hepatoblastoma) occur in about 5 to 10 per cent, mostly in the first 7 years, so long-term surveillance is recommended.

A clinical diagnosis of BWS is supported by three major findings, or two major findings and at least one minor finding. Assisted reproductive techniques increase risk about tenfold.

Methylation-based tests are the first step for 15q11-q13 disorders because they detect imprinting abnormalities that a karyotype or deletion test would miss. A normal karyotype does not exclude PWS or Angelman syndrome. Targeted deletion, UPD and imprinting-centre analysis then identify the mechanism, which is what determines recurrence risk.

• Paternal gene lost = Prader-Willi; maternal gene lost = Angelman. Check which parent is mentioned before choosing.
• Maternal UPD 15 = Prader-Willi; paternal UPD 15 = Angelman.
• First test is DNA methylation analysis, not karyotype; FISH or microarray identifies a deletion later.
• Angelman with normal methylation points to a UBE3A mutation.
• Hyperphagia and obesity are later PWS features; neonates are hypotonic.
• Deletion is the commonest mechanism (about 70 per cent) in both; UPD is a more important cause in PWS than in Angelman.
• BWS = 11p15, macroglossia, Wilms tumour risk; do not confuse with the chromosome 15 syndromes.