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Saint Mary's, United Kingdom

Bochukova E.G.,University of Cambridge | Keogh J.,University of Cambridge | Henning E.,University of Cambridge | Purmann C.,University of Cambridge | And 6 more authors.

Obesity is a highly heritable and genetically heterogeneous disorder. Here we investigated the contribution of copy number variation to obesity in 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay. Large (>500 kilobases), rare (<1%) deletions were significantly enriched in patients compared to 7,366 controls (P<0.001). We identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls. We identified five patients with overlapping deletions on chromosome 16p11.2 that were found in 2 out of 7,366 controls (P <5×-10-5). In three patients the deletion co-segregated with severe obesity. Two patients harboured a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism and mental retardation; both of these patients had mild developmental delay in addition to severe obesity. In an independent sample of 1,062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1, which is known to be involved in leptin and insulin signalling. Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity. © 2010 Macmillan Publishers Limited. All rights reserved. Source

Wraith J.E.,Genetic Medicine
Handbook of Clinical Neurology

The mucopolysaccharidoses (MPS) and mucolipidoses (ML) are progressive storage disorders that share many clinical features varying from facial dysmorphism, bone dysplasia, hepatosplenomegaly, neurological abnormalities, developmental regression, and a reduced life expectancy at the severe end of the clinical spectrum to an almost normal clinical phenotype and life span in patients with more attenuated disease.MPS and ML are transmitted in an autosomal recessive manner, except for the X-linked MPS II (Hunter syndrome). Diagnosis is initially by detecting partially degraded GAG or oligosaccharide in urine and confirmed by specific enzyme assays in serum, leukocytes, or skin fibroblasts.For the majority of disorders treatment is palliative, but there have been important advances in the use of specific enzyme replacement therapy strategies for some MPS disorders and this is an area of very rapid development. In addition, hematopoietic stem cell transplantation (HSCT) can improve outcome in carefully selected patients with MPS (especially MPS IH, Hurler syndrome), but this procedure is associated with significant risk. Gene augmentation/transfer using a variety of vectors has been successful in animal models but has not yet been successfully performed in a human patient with one of these disorders.It is important to remember that prenatal diagnosis is possible for all of these disorders. © 2013 Elsevier B.V. Source

Langford-Smith K.,University of Manchester | Arasaradnam M.,University of Manchester | Wraith J.E.,Genetic Medicine | Wynn R.,Bone Marrow Transplant Unit | And 2 more authors.
Molecular Genetics and Metabolism

Mucopolysaccharide (MPS) diseases are lysosomal storage disorders caused by deficiencies of enzymes catabolising glycosaminoglycans (GAGs). Abnormal GAG accumulation leads to symptoms including severe progressive neurological decline, skeletal deformities, organomegally, respiratory compromise and premature death. Treatment is available for some MPS diseases; enzyme replacement therapy for MPS I, II and VI, and haematopoietic stem cell transplantation for MPS I, VI and VII. These treatments are reliant on early diagnosis of the disease and accurate monitoring of treatment outcomes. Blood enzyme levels and total urinary GAGs are commonly used biomarkers in diagnosis of MPS but are not good measures of treatment outcome. Serum heparin cofactor II-thrombin complex (HCII-T), which is a GAG regulated serpin-protease complex, has recently been identified as a promising biomarker for MPS diseases. Here we present an assessment of the HCII-T biomarker in mouse models of MPS I, IIIA and IIIB, which suggests that HCII-T is a reliable marker for MPS I when measured in serum or dried blood spots stored for over a year at 4 °C, but that murine MPS IIIA and IIIB cannot be reliably detected using this biomarker. We also show that HCII-T formation in vivo is dependent on the presence of excess intravenous dermatan sulphate (DS), whilst intravenous heparan sulphate (HS), does not promote complex formation effectively. This suggests that HCII-T will prove effective as a biomarker for MPS I, II, VI and VII diseases, storing dermatan sulphate but may not be as appropriate for MPS III, storing heparan sulphate. With careful sample preparation, HCII-T ELISA could prove to be a useful biomarker for both newborn screening and measurement of treatment outcomes in selected MPS diseases. © 2009 Elsevier Inc. All rights reserved. Source

Berwouts S.,Catholic University of Leuven | Morris M.A.,University of Geneva | Girodon E.,Service de Biochimie et Genetique | Schwarz M.,Genetic Medicine | And 2 more authors.
Human Mutation

Currently, two nomenclature systems are in use to describe sequence variants for cystic fibrosis: the established traditional nomenclature system and the more recent Human Genome Variation Society (HGVS) nomenclature system. We have evaluated the use of both systems in the laboratory reports of 217 participants in the cystic fibrosis external quality assessment scheme of 2009. The mutation c.1521-1523delCTT (p.Phe508del, F508del) was described by traditional and HGVS nomenclature by 32 of 216 (15%) laboratories that correctly identified the mutation, whereas 171 (79%) laboratories used traditional nomenclature only and 13 (6%) laboratories used HGVS nomenclature only. Overall, 29 of 631 (5%) reports used nomenclature that was evaluated as being seriously incorrect and/or misleading and 136 (22%) reports contained attempts at HGVS coding, of which 104 (76%) contained no coding errors; just 33 (24%) mentioned the correct cDNA name and cited the nucleotide reference sequence. We recognized an urgent need for more consistent and correct usage of nomenclature. We recommended that cystic fibrosis transmembrane conductance regulator testing reports should include a description of the identified sequence variants in both HGVS and traditional nomenclature and provided basic recommendations and other guidance. ©2011 Wiley Periodicals, Inc. Source

Berwouts S.,Catholic University of Leuven | Girodon E.,Service de Biochimie et Genetique | Schwarz M.,Genetic Medicine | Stuhrmann M.,Institute For Humangenetik | And 2 more authors.
European Journal of Human Genetics

Participation in external quality assessment (EQA) is a key element of quality assurance in medical laboratories. In genetics EQA, both genotyping and interpretation are assessed. We aimed to analyse changes in the completeness of interpretation in clinical laboratory reports of the European cystic fibrosis EQA scheme and to investigate the effect of the number of previous participations, laboratory accreditation/certification status, setting and test volume. We distributed similar versions of mock clinical cases to eliminate the influence of the difficulty of the clinical question on interpretation performance: a cystic fibrosis patient (case 1) and a cystic fibrosis carrier (case 2). We then performed a retrospective longitudinal study of reports over a 6-year period from 298 participants for case 1 (2004, 2008, 2009) and from 263 participants for case 2 (2006, 2008, 2009). The number of previous participations had a positive effect on the interpretation score (P<0.0001), whereas the laboratory accreditation/certification status, setting and test volume had no effect. Completeness of interpretation improved over time. The presence of the interpretation element 'requirement for studying the parents to qualify the genotype' increased most (from 49% in 2004 to 93% in 2009). We still observed room for improvement for elements that concerned offering testing for familial mutations in relatives and prenatal/preimplantation diagnosis (16% and 24% omission, respectively, for case 1 in 2009). Overall, regular participation in external quality assessment contributes to improved interpretation in reports, with potential value for quality of care for patients and families by healthcare professionals involved in genetic testing. © 2012 Macmillan Publishers Limited All rights reserved. Source

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