Endocrine and metabolism

This subdomain comprises: 1) Familial early-onset obesity 2) Familial extreme low body weight 3) Lipodystrophic syndromes 4) Disorders of triglyceride metabolism

These are all illnesses sin which severe, early-onset forms cause considerable morbidity and mortality and where much of the genetic aetiology remains unknown. They also represent illnesses which provide an opportunity to gain biological insights into pathways of great potential relevance for common disorders of major public health significance, such as obesity, insulin resistance, diabetes, hyperlipidaemia and cardio-metabolic risk.

We will develop and implement bioinformatics algorithms and pipelines to categorise rare, severe inherited metabolic and endocrine disorders into homogeneous phenotypic groups. This will improve gene identification, assist genotype-phenotype correlations and future stratification prior to intervention studies.

Defining the genetic aetiology of monogenic diabetes is important to improve diagnosis and clinical care of patients and also gives critical scientific insights. For the commonest causes of MODY or neonatal diabetes there are specific treatment requirements meaning that diagnostic testing is now part of routine clinical care. The majority of monogenic diabetes result in beta-cell dysfunction: the definition of genes has defined pathways which are critical in beta-cell development, beta-cell destruction or beta-cell dysfunction giving biological insights of potential relevance for Type 2 diabetes. There are still many patients (c30-40%) with phenotypes suggestive of monogenic diabetes (neonatal diabetes, familial diabetes and developmental syndromes including diabetes) that do not have mutations in the known genes showing there are still monogenic forms of diabetes to be discovered.

Inborn Errors of Metabolism (IEM) is a very diverse group of disorders (currently more than 600 individual genes are known to cause IEMs) that can be caused by defects in biochemical pathways located in different intracellular compartments such as peroxisomes, lysosomes, mitochondria or be due to the individual organellar biogenesis defects. Many of these disorders result in neurological deficit, which can be prevented if the condition is diagnosed early. Moreover, in approximately 50% of cases with characteristic clinical picture of IEM the genetic aetiology remains unknown. There is an opportunity to gain biological insights into pathways of great potential relevance for common disorders of major public health significance, such as neurodegenerative disorders and metabolic syndrome.

This subdomain encompasses a range of endocrine disorders, in each of which members of the GeCIP have internationally recognised expertise and strong track records of genetic research: 1) Congenital adrenal hypoplasia 2) Familial or syndromic hypoparathyroidism 3) IUGR and IGF abnormalities 4) Disorders of sex development (release pending) 5) Early onset familial premature ovarian failure (release pending) 6) Congenital hypothyroidism (submitted) 7) Isolated hypogonadotrophic hypogonadism (submitted) 8) Primary hyperandrogenism (submitted) 9) Thyroid Hormone Resistance (in preparation)