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Ostergaard P.,St Georges, University of London | Simpson M.A.,Kings College London | Mendola A.,Catholic University of Louvain | Vasudevan P.,Royal Infirmary | And 22 more authors.
American Journal of Human Genetics | Year: 2012

We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures. © 2012 The American Society of Human Genetics. Source


Parker M.,Sheffield Clinical Genetics Service | Bitner-Glindzicz M.,University College London
Postgraduate Medical Journal | Year: 2015

Permanent childhood sensorineural hearing loss, is one of the most common birth defects in developed countries. It is important to identify the aetiology of hearing loss for many reasons, as there may be important health surveillance implications particularly with syndromic causes. Non-syndromic sensorineural hearing loss is a highly heterogeneous genetic condition, meaning that it may be caused by any one of numerous genes, with very few phenotypic distinctions between the different genetic types. This has previously presented significant challenges for genetic testing. However, the introduction of new technologies should enable more comprehensive testing in the future, bringing significant benefits to more affected children and their families. © 2015, BMJ Publishing Group. All right Reserved. Source


Parker M.J.,Sheffield Clinical Genetics Service | Parker M.J.,University of Oxford | Teasdale K.,Looked after and Adoptive Childrens Health Team
Archives of Disease in Childhood | Year: 2016

Looked after children are recognised as generally having greater health needs than their peers. There are numerous potential causes, environmental and genetic, and the aetiology is often multifactorial. Assessments, especially clinical genetic ones, may be limited if the information available is incomplete or not shared. There have been some exciting recent advances in diagnostic genetic testing and more are on the horizon. However, we are currently only able to make a genetic diagnosis in less than half of patients, even when both parents are available for comparative testing. There may, therefore, remain an inevitable degree of residual uncertainty about the genetic contribution to a particular child's problems. There are increasing societal pressures for genetic information to be made available to individuals in general. However, there are significant considerations in carrier/predictive testing in children and we would maintain that looked after children should not be treated differently to other children in this regard, unless there is a compelling 'best interest' justification for so doing. Diagnostic criteria exist for fetal alcohol syndrome and other embryopathies and should be applied. Such should be considered as diagnoses of exclusion, so a child should not be prematurely labelled with these conditions, without fully assessing for the contribution of other factors, genetic or otherwise. Source


Parker M.,Sheffield Clinical Genetics Service | Bitner-Glindzicz M.,University College London
Archives of Disease in Childhood | Year: 2015

Permanent childhood sensorineural hearing loss, is one of the most common birth defects in developed countries. It is important to identify the aetiology of hearing loss for many reasons, as there may be important health surveillance implications particularly with syndromic causes. Non-syndromic sensorineural hearing loss is a highly heterogeneous genetic condition, meaning that it may be caused by any one of numerous genes, with very few phenotypic distinctions between the different genetic types. This has previously presented significant challenges for genetic testing. However, the introduction of new technologies should enable more comprehensive testing in the future, bringing significant benefits to more affected children and their families. © 2015, bmj publishing group. All rights reserved. Source


Grozeva D.,University of Cambridge | Carss K.,Wellcome Trust Sanger Institute | Spasic-Boskovic O.,University of Cambridge | Parker M.J.,Sheffield Clinical Genetics Service | And 12 more authors.
American Journal of Human Genetics | Year: 2014

To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations - four nonsense (c.1195A>T [p.Lys399&z.ast;], c.1333C>T [p.Arg445&z.ast;], c.1866C>G [p.Tyr622&z.ast;], and c.3001C>T [p.Arg1001&z.ast;]) and three frameshift (c.2177-2178del [p.Thr726Asnfs&z.ast;39], c.3771dup [p.Ser1258Glufs&z.ast;65], and c.3856del [p.Ser1286Leufs&z.ast;84]) - were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID. © 2014 The American Society of Human Genetics. Source

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