Computational Modelling Group

Imprinting Disorders Finding Out Why

3rd December 2007
Karen Temple

Genetic imprinting alters gene expression by parent of origin. Neonatal diabetes is an example of an imprinting disorder due to aberrant imprinting on chromosome 6


To understand:-

  • more about why epigenetic events occur
  • whether imprinting aberrations involve more than one location simultaneously
  • the phenotype accompanying genotypes if abnormalities are found
  • development of robust tests for imprinting disorders for NHS service


Recent work has shown that imprinted genes are essential for normal human development. Imprinting refers to the regulation (the turning on and off) of genes depending on which parent they were inherited from. There are approximately 80 known human imprinted genes. These genes function as part of a network and epigenetic aberrations of their molecular controlling regions may be an important cause of developmental abnormality.

Our recent study (Mackay et al., Hum Genet. 2006 Sep;120(2):262-9 ) has shown that epigenetic changes at imprinting loci are a cause of congenital malformations, learning difficulties and developmental delay. Clinical features are wide-ranging and include: - verbal dyspraxia, growth retardation, genital abnormality and hemihypertrophy, all common reasons for referral to the service.

Research Plan

  1. Establish a cohort of patients with imprinting disorders by recruiting patients with a wide range of developmental disorders referred to the clinic ( fulfilling testing criteria)
  2. Molecular analysis of imprinted regions
  3. Correlate molecular and clinical findings
  4. Translation to NHS service


Recruitment A. Participants will be recruited in one of three ways:- 1. Patients seeking or having sought diagnosis for unexplained growth or developmental disorder attending paediatric or genetic clinics in NHS hospitals 2. Patients referred to the Wessex Genetics Laboratory for investigation of an imprinting abnormality 3. Patients known to have an imprinting aberration in at least one imprinted locus

Inclusion Criteria

Inclusion criteria are unexplained short stature <10th centile or 3 or more of the following features:-
Growth disturbance - overgrowth at birth for gestational age – weight or length>90th centile; small for gestational age weight or length <10th centile; asymmetric growth obvious clinically; unexplained postnatal excessive weight or height (>98th centile); central obesity; Developmental delay - learning difficulties; verbal dyspraxia, hypotonia; Glycaemic control - unexplained hyper or hypoglycaemia Congenital abnormalities - umbilical developmental defect, macroglossia, micrognathia, genital abnormality, scoliosis, deafness, other congenital abnormality; Conception - monozygous twinning, conceived by assisted reproductive technology.

AND must have normal routine investigations including chromosome and/or array analysis and no known cause for the problems

OR a known imprinting disorder diagnosed or confirmed in an accredited NHS genetics laboratory

B. Families will be invited to opt into the study with an information sheet. This will be available in clinic or can be sent out to suitable patients by the clinic physician or to the referring clinician of the laboratory C. Written consent will be obtained (either in the follow up clinic or sent back afterwards) and will include consent to access the medical records D. Participating physicians will be asked to complete a concise clinical information questionnaire, and obtain blood samples which will be sent to the Wessex Genetics Laboratory E. Patients with a known imprinting abnormality will be offered a clinic appointment in Southampton. History, examination, photos, blood sample and urine samples will be taken by Prof Karen Temple, or trained specialist registrar or referring physician.

Molecular investigation

Molecular investigation will be staged:-

Detailed epigenetic and genetic analysis of the known imprinting control centres and their clustered genes designed to build a comprehensive picture of the extent of aberrant imprinting.

Feedback to participants

Normal results will be communicated by post to patients and the referring clinician after the analysis of the known imprinting regions.

For patients with abnormal results, the patient and referring clinician plus GPs if consent given, will be informed first by letter. Patients will then be contacted by phone and invited to attend a research clinic if they have not been seen already (see E). The clinic visit will be offered in Southampton unless this is not possible when it will be conducted with the aid of the referring doctors.

Routine history, examination, photos and blood, urine and spit samples will be taken by Dr Karen Temple, or trained specialist registrar or referring physician. Parental samples (where possible) may be requested to facilitate further investigation of the epigenetic results. Clinical notes will be reviewed and standard auxological data will be obtained (including height and weight SDS and birth weight SDS) if not available to the clinician.

Where indicated the patient will be referred to their local clinical geneticist so that the clinical implications of the findings can be discussed in an NHS setting and long term follow up established.

This study has been reviewed by the Southampton and South West Hampshire Research Ethics Committee A.

Ethics approval number 07/H0502/85


Life sciences simulation: Biomedical, Developmental Biology, Epigenetics, NextGen Sequencing