Hypomethylation Syndrome

This was first described by the Wessex Imprinting group in 2006 and is currently being actively investigated. It was discovered because patients with transient neonatal diabetes due to loss of methylation at 6q24 ( see TND) were subsequently found to have a generalised but variable loss of methylation at several maternally imprinted loci including the Beckwith Wiedemann locus at 11p15.5, the Pseudohypoparathyroid locus at 20q13 and other loci where a clinical phenotype is currently not recognised .

Clinical Findings

Concomitant with the variable mosaic loss of methylation are variable clinical features. While the cardinal finding in cases reported so far is Transient Neonatal Diabetes this may be due to ascertainment bias.

Other features have been noted in more than one patient and include:-

• Prenatal growth deficiency
• Macroglossia
• Umbilical Hernia
• Congenital cardiac anomaly
• Minor hand abnormalities such as clinodactyly
• Developmental delay. (In two patients this has been severe and associated with hypoplasia of the corpus callosum, cerebral blindness and in one profound hearing loss.)

Siblings have been reported. This condition is likely to be autosomal recessively inherited in some families An epigenotype/phenotype may emerge.

Testing

Study patients will have epigenetic testing at multiple imprinted loci to determine if this is contributing to the phenotype. This is provided free of charge as it is funded by research funding.

We would strongly recommend taking blood or DNA from both parents as well as the child, as this will allow us to rapidly establish the inheritance pattern which is particularly important in imprinting disorders. Furthermore it will provide evidence of whether a genetic finding has risen de novo.

To send with samples

When you send us a sample for genetic testing please send us all details on our Testing Criteria form these include:

• Referring clinician details
• Patient Details
• General Presentation
• Current status of Patient

• Any other clinical features

Send the sample to:-

Dr Deborah Mackay
Lecturer in Human Genetics
Wessex Imprinting Group
Division of Human Genetics
Wessex Genetics Laboratory
Salisbury Health Care Trust
Salisbury
SP2 8BJ
djgm@soton.ac.uk ( email Deborah to tell her the sample is on route)
tel 01722 425048

And clinical details can be discussed with

Dr Karen Temple
Prof of Medical Genetics
and Honorary Consultant in Clinical Genetics
Academic Unit of Genetic Medicine
Princess Anne Hospital
Coxford Road
Southampton
SO16 5YA
ikt@soton.ac.uk
tel 02380 796625

For more information on genetic testing please look at the genetic testing section on this website.

Consent

When taking samples you should get written consent for the testing - as with any genetic test. 

 

References

• Mackay DJ, Boonen SE, Clayton-Smith J, Goodship J, Hahnemann JM, Kant SG et al. A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus. Hum Genet 2006; 120(2):262-269.
• Mackay DJ, Hahnemann JM, Boonen SE, Poerksen S, Bunyan DJ, White HE et al. Epimutation of the TNDM locus and the Beckwith-Wiedemann syndrome centromeric locus in individuals with transient neonatal diabetes mellitus. Hum Genet 2006; 119(1-2):179-184.
• Boonen SE, Porksen S, Mackay DJ, Oestergaard E, Olsen B, Brondum-Nielsen K et al. Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings. Eur J Hum Genet 2008; 16(4):453-461.