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By utilising genomic information through linkage studies and next-generation sequencing, we aim to identify new genes to help improve our understanding of the mechanistic basis of human diseases.

Our centre has a particular interest in the analysis inherited cardiac diseases, vascular disorders, pulmonary arterial hypertension (PAH), lymphatic diseases, neurodegenerative, mitochondrial, metabolic and the developmental disorder Adams-Oliver syndrome (AOS).

The Lymphovascular Research Unit

The Lymphovascular Research Unit focuses on identifying the genetic basis of various forms of primary lymphoedema. Lymphoedema is the chronic swelling of one or more body parts, most commonly an arm or leg. Unravelling the genetic basis of this disorder will help us improve diagnostics and therapeutic decision-making. 

The unit, led by Dr Pia Ostergaard, includes several other MCS academics: Professor Steve Jeffery and clinicians Professor Sahar Mansour, Professor Peter Mortimer and Dr Lakshmi Ratnam, as well as other researchers.

Genetics of childhood-onset neurodegenerative diseases

Ataxia is a neurological condition affecting coordination, speech and balance. Dr Christopher Carroll's team is investigating the genetic basis of paediatric-onset ataxias using whole-exome and whole-genome sequencing. Mutations in genes involved in mitochondrial metabolism are a frequent cause in this disease.

His team has discovered novel disease genes underlying paediatric-onset ataxias including the autophagy receptor SQSTM1/P62 (Haack, Ignatius et al AJHG 2016) and GPAA1 (Nguyen TTM et al AJHG 2017) in collaboration with paediatric neurologists Pirjo Isohanni (MD PhD) and Tuula Lönnqvist (MD PhD) at Helsinki University Children’s Hospital.

Genetics of cardiomyopathy

We have recently identified mutations in the KLHL24 gene as being responsible for causing cardiomyopathy in two unrelated families. These findings can be used for diagnostic testing of individuals with symptoms similar to those described in the study, and where the gene responsible for their condition is not known. If KLHL24 is found to be the faulty gene, patients will get better guidance and more accurate information on their condition.

Genetics of vascular disorders

Dr Laura Southgate’s research focuses on the analysis of genetic risk factors predisposing to inherited vascular disorders with a complex aetiology, including cluster headache, pulmonary arterial hypertension (PAH) and the developmental disorder Adams Oliver Syndrome (AOS).

PAH is a progressive vascular disorder of dysregulated cell growth, which is often fatal. Mutation of the BMPR2 gene represents the main genetic driver. AOS is a genetically heterogeneous disorder characterised by scalp cutis aplasia and limb truncation defects, often associated with congenital cardiovascular abnormalities. To date, Dr Southgate and others have identified six genes highlighting Rho GTPase dysregulation and perturbed Notch signalling as prominent risk factors in AOS. Her current work aims to provide further insight into the fundamental processes disrupted, through the identification of additional disease genes and examining the impact of pathogenic mutations on vascular development.

Overgrowth-intellectual disability study

Overgrowth-intellectual disability (OGID) syndromes are a group of conditions characterized by increased height and/or head circumference (≥2SD) in association with an intellectual disability. This study, led by Professor Kate Tatton-Brown, has recruited over 2000 patients with OGID, identified new genes (DNMT3A, EZH2, PPP2R5D, and HIST1H1E), defined new clinical syndromes and translated the findings into clinical practice.

The work, in partnership with St. George’s NHS Trust, will be using the very latest genomic technologies and bioinformatics to investigate new genetic causes of OGID syndromes and define associated clinical presentations and natural history of these conditions. These findings in turn will be integrated into clinical practice, informing patient management and genetic testing opportunities through NHS diagnostic laboratories.

 

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