Zunera Bashir, Grace Shallis & Zia Afrin

A novel autosomal recessive chromosome breakage syndrome known as LICS; Lung disease, Immunodeficiency, Chromosome Instability Syndrome has been identified by Dr Jo Murray and her team at the Genome Damage and Stability Centre at the University of Sussex with the help of researchers from the Netherlands and the United States.

LICS is a primary immunodeficiency disorder that leads to the premature death of infants.

It is linked to missense mutations — these are changes in DNA that lead to coding for a different amino acid in the protein — in NSMCE3, a subunit of the SMC5/5 complex.

This complex is important for correct repair of double strand breaks in DNA by coding for specific proteins structures necessary for repair.

It also has implications for survival of replication stress- problems during replication that if not repaired correctly can lead to mutations or chromosome rearrangements.

Researchers at the GDSC showed that in cells from affected individuals the SMC5/6 complex was destabilised and this led to an inability to repair DNA damage and chromosome instability.

The clinical symptoms of LICS are characterised by a failure to thrive from around 4 months, followed by severe lung disease ultimately leading to death at around one year of age. Patients had combined T Cell and B Cell immunodeficiency, meaning their immunity responses failed.

The patients were able to mount an immune response to initial vaccinations but were unable to respond to booster vaccinations.

LICS is a rare autosomal recessive genetic disorder so affected children must inherit two altered genes, one from each parent. Therefore, the risk of the disease being present in offspring increases with parent relatedness.

It was originally identified in a Dutch and unrelated American family, but since publication of the syndrome a number of other families with multiple affected offspring have been identified in the Netherlands, all presenting with similar clinical symptoms of failure to thrive, terminal lung disease and immunodeficiency.

The next step with our findings on LICS is to raise awareness of this research in order to gather data of the frequency of this rare disease in the UK and identify families that may be at risk.

Families where more than onr child died of pulmonary disease following pneumonia are likely candidates and looking for this trend will help to identify patients and families at risk. With more families, researchers will also be able to further understand the effects of mutations causing the disease and develop assays for diagnosis and potentially treatment for those affected.

Part of the School of Life Sciences, the GDSC is an internationally recognised centre of research that focuses on understanding how problems in the DNA are repaired and the consequences for mis-repair on genetic diseases and cancer.

If you are interested in finding out more about LICS and the research of Dr. Murray and her team, full details of LICS syndrome can be found in van der Crabben et al, Journal of Clinical Investigation, 2016. Alternatively, you can contact Jo Murray at j.m.murray@sussex.ac.uk

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