Endocrine Abstracts

Introduction: Genetic projects, such as 100KGenomes, are identifying a vast amount of genetic variants that require interpretation. Several variants lack sufficient evidence to be classified as neutral or damaging. Such variants are annotated as ‘unclassified’ and interpretation of their biological effect is of paramount importance, but remains a major challenge. Variant predictors are widely used to prioritize variants for further studies...

Introduction: Genetic projects, such as 100KGenomes, are identifying a vast amount of genetic variants that require interpretation. Several variants lack sufficient evidence to be classified as neutral or damaging. Such variants are annotated as ‘unclassified’ and interpretation of their biological effect is of paramount importance, but remains a major challenge. Variant predictors are widely used to prioritize variants for further studies...

Background: In the UK, NICE guidelines for familial hypercholesterolaemia (FH) recommend a greater than 50% reduction in low-density lipoprotein-cholesterol (LDL-C) as the therapeutic target. However, despite the availability of a range of lipid lowering medication, this target is often difficult to achieve and, more importantly, maintain life-long. Understanding factors that affect LDL-C target achievement is key to reducing cardiovascular disease (CVD) risk. Currently, there...

Background: Cardiovascular disease (CVD) risk in familial hypercholesterolaemia (FH) is driven by cumulative exposure to high low-density lipoprotein cholesterol (LDL-C) levels. Previously, LDL-C burden has been loosely approximated using the cholesterol year score (CYS) based on two LDL-C readings only. We aimed to determine whether a more sophisticated LDL-C burden score based on serial LDL-C measurements, could more accurately predict major atherosclerotic cardiovascular ev...

Background: Lipoprotein(a) (Lp(a)) is an independent, causal, genetic risk factor for cardiovascular disease (CVD). Coronary artery calcium (CAC), measured by computerised tomography (CT) scans, is a known marker for atherosclerosis. CT Agatston scores, also known as CAC scores, are thought to be better predictors of CVD than traditional risk factors. There is conflicting data regarding the relationship between Lp(a) levels and CAC. A preliminary study has suggested a positive...

Nicotinamide nucleotide transhydrogenase (NNT) is an integral protein of the inner mitochondrial membrane and plays a major role in maintaining the redox balance by catalysing the trans-hydrogenation between NADH and NADP+ and proton translocation across the mitochondrial membrane.Genetic variants in NNT have recently been reported in patients with familial glucocorticoid deficiency (FGD), combined mineralocorticoid and glucocorticoid deficiency...

GHI is a genetic condition in which patients present with growth failure due to primary IGF1 deficiency caused by a defect in the GH-IGF1 axis. In the last 10 years in the Centre for Endocrinology of WHRI at Barts and the London, 24 causative mutations in genes of the GH–IGF1 axis have been determined in 58 patients (Table 1). STAT5B mutations were responsible in 2 cases, IGFALS in 4 but the majority of defects identified were in GHR. Most mutations identifi...

Background: The initiation of puberty is heralded by increasing gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. During embryonic life the GnRH neuroendocrine network develops thanks to a coordinated migration of neurons from the nasal placode to the forebrain. Our group has previously demonstrated that dysregulation in GnRH neuronal migration leads to delayed pubertal onset. Late puberty affects up to 2% of the population and is associated with adverse h...

Inherited growth hormone insensitivity (GHI) is usually caused by mutations in the GH receptor (GHR). Patients present with short stature associated with a mid-facial hypoplasia (Laron facial features) or with normal facial appearance. We previously described an intronic mutation in the GHR gene (A−1 to G−1 substitution in intron 6) resulting in the activation of a pseudoexon (6Ψ) in four related GHI patients with normal facial fea...

Whilst several key genetic contributors to the phenotype of central precocious puberty (CPP) have been recognized, many familial cases remain without a clear genetic aetiology. Methyl-CpG-binding protein 2 (MECP2) is a chromatin-associated transcriptional regulator, which plays an essential role in neuronal maturation. It is encoded by the MECP2 gene, located at chromosome Xq28, which is highly expressed in brain tissues. Loss-of-function mutations in MECP2 are usually associa...