Intellectual Disability
Research investigating chromosome deletion in Kabuki syndrome, an intellectual handicap
Overview
Around two per cent of the UK population have some degree of intellectual disability. The different disorders have a variety of causes and some have a high risk of recurrence in families.
Our researchers have initiated new clinical trials using our new technology platforms for precise diagnosis for affected patients, of the causes of their disabilities. Their findings have been rapidly translated into improved diagnostic techniques in the NHS service. By pinpointing the exact genetic causes of groups of rare disorders we have unravelled new chemical pathways in the cells of the body which we hope will lead to more effective treatments.
Researchers have also instigated a programme to develop management guidelines for rare diseases by adapting validated methodologies. These guidelines are now available for professionals and patients.Problem
Kabuki syndrome (KS) is a rare but serious disorder that affects around 1 in 10,000 children. As well as moderate or severe learning disability, health problems include heart defects and cleft palates. The underlying cause was not known and, apart from genetic specialists, few doctors had experience of diagnosis or caring for such children. Many affected children had to undergo extensive investigations and hospital admissions before a diagnosis was made. Their parents felt isolated and concerned about appropriate care for the affected child and about risks to other family members.
What we have achieved to date
Our researchers conducted a study involving over one hundred KS patients. Firstly patients’ chromosomes were examined to determine if deletions or duplications of chromosome material were responsible for KS. When no clues were detected we examined individual ‘candidate’ genes. Ultimately collaborative work with colleagues in Seattle identified MLL2 as a likely causative gene through using the next generation sequencing technique. Alongside this we undertook a translational research study to optimise, streamline and quality assure a diagnostic test to be introduced into the NHS. This has now been accepted onto the UK Genetic Testing Network PortfolioOur researchers, with support from families with affected children, began a programme of research to pinpoint the underlying cause of Kabuki Syndrome. An expert group has also been set up to examine the published literature and devise management guidelines to help in the ongoing care of sufferers.
Our research also focuses on the medical needs of KS patients. Guideline for management of KS have been developed and disseminated to genetic centres in the UK and Europe so that they can be given to newly diagnosed families, their paediatricians and primary care physicians to ensure appropriate care. Shorter versions have also been incorporated into patient-held records to allow parents to inform education and social care agencies about their child’s medical condition and needs.
What we aim to achieve
Following identification of the MLL2 gene new insights into pathogenesis have been gained since KS is one of a number of multiple malformation/intellectual disability syndromes. This is due to mutations of genes involved in controlling how DNA is folded and how expression of genes is regulated. This work is continuing and the link between specific mutations and the problems in individual KS patients are being studied.
