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Clayton-Smith J.,University of Manchester | Clayton-Smith J.,Manchester Biomedical Research Center | Giblin C.,University of Manchester | Smith R.A.,Rochdale Infirmary | And 2 more authors.
Clinical Dysmorphology

The 3q29 microdeletion syndrome is caused by a recurrent 1.6 Mb deletion of the 3q subtelomeric region. Though sometimes visible on routine microscopy, the deletion is detected more reliably using subtelomeric fluorescence in-situ hybridization (FISH) or molecular karyotyping. The clinical features associated with a 3q29 microdeletion are variable and include developmental delay, autistic features, skeletal abnormalities and dysmorphic facial features with a relatively long face, long nose with a high bridge and broad tip, short philtrum and large ears. Orofacial clefting, cardiac defects, ocular anomalies and genitourinary malformations have been reported occasionally. We report a three generation family where four individuals were confirmed to have a 3q29 microdeletion and compare their clinical features to those of previously reported patients. This family shows that the learning difficulties associated with a 3q29 deletion may be relatively mild. The history of a severe depressive disorder commencing in adulthood in the affected grandmother also supports previous studies linking the 3q29 region to bipolar disorder and links with the observation of Digilio et al. (2009) who also reported a history of depression in an adult woman with a similar deletion. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Heazell A.E.P.,University of Manchester | Heazell A.E.P.,Manchester Biomedical Research Center | Bernatavicius G.,University of Manchester | Warrander L.,University of Manchester | And 2 more authors.
Reproductive Sciences

Metabolomics offers a powerful holistic approach to examine the metabolite composition of biofluids to identify disruptions present in disease. We used ultra performance liquid chromatography-mass spectroscopy on the maternal serum obtained in the third trimester to address the hypothesis that pregnancies ending in poor outcomes (small for gestational age infant, preterm birth, or neonatal intensive care admission, n = 40) would have a different maternal serum metabolic profiles to matched healthy pregnancies (n = 40). Ninety-eight identified metabolic features differed between normal and poor pregnancy outcomes. Classes of metabolites perturbed included free fatty acids, glycerolipids, progesterone metabolites, sterol lipids, vitamin D metabolites, and sphingolipids; these highlight potential molecular mechanisms associated with pregnancy complications in the third trimester linked by placental dysfunction. In this clinical setting, metabolomics has the potential to describe differences in fetoplacental and maternal metabolites in pregnancies with poor pregnancy outcomes compared with controls. © The Author(s) 2012. Source

Payne K.,University of Manchester | Fargher E.A.,Bangor University | Roberts S.A.,University of Manchester | Tricker K.,University of Manchester | And 4 more authors.
Value in Health

Objective: The study compared the preferences of patients and health-care professionals for the key attributes of a pharmacogenetic testing service to identify a patient's risk of developing a side effect (neutropenia) from the immunosuppressant, azathioprine. Methods: A discrete choice experiment was posted to a sample of patients (n=309) and healthcare professionals (HCPs) (n=410), as part of the TARGET study. Five attributes, with four levels each, described the service as follows: level of information given; predictive ability of the test; how the sample is collected; turnaround time for a result; who explains the test result. Data from each sample were first analyzed separately and responses were compared by 1) identifying the impact of the scale parameter, and 2) estimating marginal rates of substitution. Results: The final analysis included 159 patients and 138 HCPs (50% & 34% response rates). Estimated attribute coefficients from the patient and HCP sample differed in size, after taking into account the impact of the scale parameter. Patients and HCPs had similar preferences for predictive accuracy of the test and were willing to wait 2 days for a 1% improvement in test accuracy. Patients preferred to obtain more information and were willing to wait 19 days compared to 8 days for HCPs for providing higher levels of information. Conclusions: Patients demanded accurate and timely information from health-care professionals about why it was necessary to have a pharmacogenetic test and what the test results mean. In contrast, health-care professionals appear to focus more exclusively or entirely upon the predictive accuracy and waiting time for a test result. Copyright © 2011, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. Source

Green J.,University of Manchester | Green J.,Manchester Biomedical Research Center | Charman T.,Institute of Education | McConachie H.,Newcastle University | And 11 more authors.
The Lancet

Background: Results of small trials suggest that early interventions for social communication are effective for the treatment of autism in children. We therefore investigated the efficacy of such an intervention in a larger trial. Methods: Children with core autism (aged 2 years to 4 years and 11 months) were randomly assigned in a one-to-one ratio to a parent-mediated communication-focused (Preschool Autism Communication Trial [PACT]) intervention or treatment as usual at three specialist centres in the UK. Those assigned to PACT were also given treatment as usual. Randomisation was by use of minimisation of probability in the marginal distribution of treatment centre, age (≤42 months or >42 months), and autism severity (Autism Diagnostic Observation Schedule-Generic [ADOS-G] algorithm score 12-17 or 18-24). Primary outcome was severity of autism symptoms (a total score of social communication algorithm items from ADOS-G, higher score indicating greater severity) at 13 months. Complementary secondary outcomes were measures of parent-child interaction, child language, and adaptive functioning in school. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN58133827. Results: 152 children were recruited. 77 were assigned to PACT (London [n=26], Manchester [n=26], and Newcastle [n=25]); and 75 to treatment as usual (London [n=26], Manchester [n=26], and Newcastle [n=23]). At the 13-month endpoint, the severity of symptoms was reduced by 3·9 points (SD 4·7) on the ADOS-G algorithm in the group assigned to PACT, and 2·9 (3·9) in the group assigned to treatment as usual, representing a between-group effect size of -0·24 (95% CI -0·59 to 0·11), after adjustment for centre, sex, socioeconomic status, age, and verbal and non-verbal abilities. Treatment effect was positive for parental synchronous response to child (1·22, 0·85 to 1·59), child initiations with parent (0·41, 0·08 to 0·74), and for parent-child shared attention (0·33, -0·02 to 0·68). Effects on directly assessed language and adaptive functioning in school were small. Interpretation: On the basis of our findings, we cannot recommend the addition of the PACT intervention to treatment as usual for the reduction of autism symptoms; however, a clear benefit was noted for parent-child dyadic social communication. Funding: UK Medical Research Council, and UK Department for Children, Schools and Families. © 2010 Elsevier Ltd. All rights reserved. Source

Lehalle D.,Manchester Biomedical Research Center | Williams C.,Florida College | Siu V.M.,University of Western Ontario | Clayton-Smith J.,Manchester Biomedical Research Center
American Journal of Medical Genetics, Part A

Pitt-Hopkins syndrome (PHS) is characterized by severe mental retardation, characteristic facial features including a wide mouth and intermittent overbreathing. It is due to abnormalities of the TCF4 gene at 18q21.1 and over 50 cases have now been reported in the literature. The clinical features overlap significantly with those of Angelman, Rett, and Mowat-Wilson syndromes. We have observed prominent fetal pads as a feature in several individuals with PHS and suggested that this is a useful clinical sign which helps to distinguish PHS from other conditions in the differential diagnosis and may guide genetic testing. © 2011 Wiley-Liss, Inc. Source

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