Gene responsible for severe congenital skin disease, Harlequin Ichthyosis, identified by Queen Mary team

The genetic cause of the devastating skin disease Harlequin Ichthyosis has been discovered by a team at Barts and the London, Queen Mary’s School of Medicine and Dentistry.

In a paper to be published online in April in the American Journal of Human Genetics, Professor David Kelsell, of Queen Mary’s Centre for Cutaneous Research, outlines the recent breakthrough.

Harlequin Ichthyosis (HI) is a rare, life threatening condition, where babies are born covered in a thick ‘coat of armour’. The skin dries out to form hard diamond shaped plaques, severely restricting their movement.

Historically, these babies usually die within two days of birth, due to feeding problems, bacterial infection and/or respiratory diseases. But a number of patients now survive, thanks to the wider availability of neonatal care, and developments in treatment.

Prof Kelsell said: “The search for the genetic cause of HI has taken more than seven years, with groups in the UK, Japan and US finding the classical linkage analysis techniques unsuccessful. This is largely down to the lethal nature of the condition and the small size of families with the condition. Our breakthrough came from applying SNP array technology.”

The relatively new SNP or ‘Snip’ array technology has made searching for disease genes a much quicker and cheaper process – one which enabled Kelsell and his team to identify the HI gene in a matter of weeks.

SNPs, or single nucleotide polymorphisms, are common but minute variations in the DNA sequence, they occur when just one of the four letters that make up the code swaps places. Each array is the size of a fingernail, and contains over 10,000 of these different SNPs. Identifying an SNP which is consistently inherited with a disease can help point researchers to the ‘linked’ gene that may be ultimately responsible for the condition.

Professor Kelsell’s team looked at individuals from twelve families who are affected with HI, three from the USA, seven from the UK and two from Italy – all from diverse ethnic backgrounds. Using SNP array technology, they were able to pinpoint the area of code responsible for HI, and discovered mutations in the ABCA12 gene that maps in this area, in 11 of the 12 patients studied.

Harlequin Ichthyosis affects a number of families in the UK, four children affected by HI, and Professor Kelsell’s discovery, will be the subject of an ITV documentary, Real Lives: the Harlequin Sisters, to be broadcast later this year.

HI is thought to be caused by a defect in the way lipids (fats) are transported and discharged into the top layers of the skin. Normally, tiny spherical grains called lamellar granules migrate upwards through the skin, depositing lipids into the intercellular spaces of the skin’s uppermost layer. These lipids act as a protective barrier against bacteria and infection.

In patients with HI, these lamellar granules are formed abnormally, the ABCA12 gene may play a critical role in their formation, explaining the defects in the epidermal barrier seen in this disorder.

Until now, pre-natal screening tests for HI were often unreliable and inconclusive, involving risky, invasive procedures such as foetal skin biopsies. Professor Kelsell added: “By identifying ABCA12, our team has provided the molecular clue towards understanding the numerous biological abnormalities seen in HI skin, and established the means for early prenatal DNA diagnosis of HI.” The team’s next step will be to investigate the role of ABCA12 in the skin with financial support from BDF: Newlife.

David Kelsell is Professor of Human Molecular Genetics at the Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London.

The work was carried out with Dr Edel O’Toole, also from the Centre for Cutaneous Research, Dr Charles Mein from the Genome Centre, and Professor Bryan Young from the Molecular Oncology Unit.

Funding came from the Wellcome Trust, the Odland Endowed Research Fund and the Barts and the London Charitable Foundation.

The Centre for Cutaneous Research

In addition to providing a significant clinical service for both general and specialist dermatology, and teaching core curriculum in undergraduate studies, the Centre for Cutaneous Research is a research leader in Europe. The focus of research is cellular and molecular biology of human skin, and associated diseases. External funding of around £1.5million is obtained yearly.

The Genome Centre at Barts and the London

The Genome Centre at Barts and the London opened in 2001 with initial funding from the Special Trustees of St Bartholomew’s and reflects the commitment of Queen Mary to genetic and genomic research. We facilitate a number of genetics and genomics projects within the College and currently seeking collaborations with a wider research community.

Queen Mary, University of London

Queen Mary is the fourth largest of the Colleges of the University of London. Its roots lie in four historic colleges: Queen Mary College, Westfield College, St Bartholomew’s Hospital Medical College and the London Hospital Medical College. Pooling strengths, expertise and resources, Queen Mary is now fully integrated.

The College currently has over 10,000 undergraduate and postgraduate students, with an academic and support staff of around 2,600. It is organised into the four faculties of Arts, Engineering and Mathematical Sciences, Law and Social Sciences, and Natural Sciences, and Barts and The London, Queen Mary’s School of Medicine and Dentistry. It is a research university, with over 80 per cent of research staff working in departments where research is of international or national excellence (RAE 2001). It has a strong international reputation, with over 20 per cent of students coming from over 100 countries.

Real Lives : The Harlequin Sisters

For more information regarding the forthcoming ITV documentary and the families concerned, please contact Joanne Farrelly, Press Officer for ITV, on 0207 261 8102 or email:

About the BDF

BDF Newlife is the UK’s leading child health and research charity. For more information visit:

The American Journal of Human Genetics