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McVeigh T.P.,Our Ladys Childrens Hospital Crumlin | Banka S.,University of Manchester | Banka S.,Manchester Center for Genomic Medicine | Reardon W.,Our Ladys Childrens Hospital Crumlin
Clinical Dysmorphology | Year: 2015

Kabuki syndrome is a rare genetic malformation syndrome that is characterized by distinct facies, structural defects and intellectual disability. Kabuki syndrome may be caused by mutations in one of two histone methyltransferase genes: KMT2D and KDM6A. We describe a male child of nonconsanguineous Irish parents presenting with multiple malformations, including bilateral extreme microphthalmia; cleft palate; congenital diaphragmatic hernia; duplex kidney; as well as facial features of Kabuki syndrome, including interrupted eyebrows and lower lid ectropion. A de-novo germline mutation in KMT2D was identified. Whole-exome sequencing failed to reveal mutations in any of the known microphthalmia/anopthalmia genes. We also identified four other patients with Kabuki syndrome and microphthalmia. We postulate that Kabuki syndrome may produce this type of ocular phenotype as a result of extensive interaction between KMT2D, WAR complex proteins and PAXIP1. Children presenting with microphthalmia/anophthalmia should be examined closely for other signs of Kabuki syndrome, especially at an age where the facial gestalt might be less readily appreciable. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Morris A.A.M.,Manchester Center for Genomic Medicine | Leonard J.V.,University College London
Paediatrics and Child Health (United Kingdom) | Year: 2015

Inborn errors of metabolism are individually rare but so many have now been described that the general paediatrician will encounter one from time to time. For many, early treatment is important. Unfortunately most that present acutely do so with non-specific symptoms and signs. It is therefore necessary to identify and investigate those at high risk. The most common problems are neurological (including coma, seizures and stroke-like episodes), hypoglycaemia, disorders of acid-base regulation, acute liver disease, rhabdomyolysis, cardiomyopathy and sudden collapse. Treatment should be started as soon as an inborn error is suspected. © 2014.

Lum S.H.,Royal Manchester Childrens Hospital | Jones S.A.,Manchester Center for Genomic Medicine | Ghosh A.,Manchester Center for Genomic Medicine | Bigger B.W.,University of Manchester | Wynn R.F.,Royal Manchester Childrens Hospital
Expert Opinion on Orphan Drugs | Year: 2016

Introduction: The mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases arising from a deficiency in the enzymes that breakdown glycosaminoglycans. They are characterised biochemically by substrate accumulation and clinically by multi-organ dysfunction and premature death. Critically, an exogenous enzyme may correct the cellular enzyme deficiency. Hematopoietic stem cell transplant (HSCT) has been used in the treatment of MPS for over 30 years.Areas covered: This paper focuses on the principle of HSCT in MPS and presents current evidence of HSCT in MPS. Factors affecting the transplant and disease outcome, as well as strategies to improve outcomes in MPS I are highlighted.Expert opinion: Transplant outcomes have hugely improved over recent decades so that most patients are expected to survive and be engrafted with donor-derived, enzyme-competent leucocytes following a transplant. The influence of an engraftment on the clinical course of the patient depends critically on the age at transplant and the enzyme dose delivered by the graft. Early therapy is best since transplant is better at preventing disease progression than reversing established disease. Some MPS are more transplant-responsive than others, and some organs respond better than others. The clinical outcome of these refractory organs and diseases may be improved beyond what is possible with wild-type donors by enhancing enzyme delivery using gene-modified, autologous cells. © 2016 Taylor & Francis.

Patton S.,Manchester Center for Genomic Medicine | Normanno N.,Cell Biology and Biotherapy Unit | Blackhall F.,Christie Hospital | Murray S.,Biomarker Solutions Ltd. | And 7 more authors.
British Journal of Cancer | Year: 2014

Background:The external quality assurance (EQA) process aims at establishing laboratory performance levels. Leading European groups in the fields of EQA, Pathology, and Medical and Thoracic Oncology collaborated in a pilot EQA scheme for somatic epidermal growth factor receptor (EGFR) gene mutational analysis in non-small-cell lung cancer (NSCLC).Methods:EQA samples generated from cell lines mimicking clinical samples were provided to participating laboratories, each with a mock clinical case. Participating laboratories performed the analysis using their usual method(s). Anonymous results were assessed and made available to all participants. Two subsequent EQA rounds followed the pilot scheme.Results:One hundred and seventeen labs from 30 countries registered and 91 returned results. Sanger sequencing and a commercial kit were the main methodologies used. The standard of genotyping was suboptimal, with a significant number of genotyping errors made. Only 72 out of 91 (72%) participants passed the EQA. False-negative and-positive results were the main sources of error. The quality of reports submitted was acceptable; most were clear, concise and easy to read. However, some participants reported the genotyping result in the absence of any interpretation and many obscured the interpretation required for clinical care.Conclusions:Even in clinical laboratories, the technical performance of genotyping in EGFR mutation testing for NSCLC can be improved, evident from a high level of diagnostic errors. Robust EQA can contribute to global optimisation of EGFR testing for NSCLC patients. © 2014 Cancer Research UK.

Bholah Z.,University of Manchester | Bholah Z.,Foundation Medicine | Smith M.J.,University of Manchester | Smith M.J.,Foundation Medicine | And 10 more authors.
Familial Cancer | Year: 2014

Gorlin syndrome is an autosomal dominant disorder characterized by multiple early-onset basal cell carcinoma, odontogenic keratocysts and skeletal abnormalities. It is caused by heterozygous mutations in the tumour suppressor PTCH1. Routine clinical genetic testing, by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to confirm a clinical diagnosis of Gorlin syndrome, identifies a mutation in 60-90 % of cases. We undertook RNA analysis on lymphocytes from ten individuals diagnosed with Gorlin syndrome, but without known PTCH1 mutations by exonic sequencing or MLPA. Two altered PTCH1 transcripts were identified. Genomic DNA sequence analysis identified an intron 7 mutation c.1068-10T>A, which created a strong cryptic splice acceptor site, leading to an intronic insertion of eight bases; this is predicted to create a frameshift p.(His358Alafs 12). Secondly, a deep intronic mutation c.2561-2057A>G caused an inframe insertion of 78 intronic bases in the cDNA transcript, leading to a premature stop codon p.(Gly854fs3). The mutations are predicted to cause loss of function of PTCH1, consistent with its tumour suppressor function. The findings indicate the importance of RNA analysis to detect intronic mutations in PTCH1 not identified by routine screening techniques. © 2014 Springer Science+Business Media Dordrecht.

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