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Kannu P.,Queens University | Kannu P.,University of Melbourne | Perry D.,Starship Children Hospital | Rees M.,The Surgical Center | And 2 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

We report on an individual affected by multiple juxtasutural cranial hyperostoses who later developed cervical spine hyperostoses with associated fusion anomalies. The propositus was not affected by a disorder of generalized overgrowth. An echocardiogram revealed areas of abnormal signal within the myocardium which were consistent with fatty infiltration on magnetic resonance imaging of the heart. We compare our case with a few previously reported cases that share phenotypic similarities but differ in some other clinical aspects. It is possible that these patients represent a phenotypic continuum resulting from a somatic mutation in an unknown gene. © 2011 Wiley-Liss, Inc. Source

Goudie D.R.,University of Dundee | D'Alessandro M.,University of Dundee | Merriman B.,University of California at Los Angeles | Lee H.,University of California at Los Angeles | And 21 more authors.
Nature Genetics | Year: 2011

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinomaĝ€"like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndromegrelated disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer. © 2011 Nature America, Inc. All rights reserved. Source

Simpson M.A.,Kings College London | Irving M.D.,Kings College London | Asilmaz E.,Kings College London | Gray M.J.,The New School | And 15 more authors.
Nature Genetics | Year: 2011

We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine- threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling. © 2011 Nature America, Inc. All rights reserved. Source

Hoischen A.,Radboud University Nijmegen | Van Bon B.W.M.,Radboud University Nijmegen | Gilissen C.,Radboud University Nijmegen | Arts P.,Radboud University Nijmegen | And 20 more authors.
Nature Genetics | Year: 2010

Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect. © 2010 Nature America, Inc. All rights reserved. Source

Kannu P.,Hospital for Sick Children | Kannu P.,University of Melbourne | Kannu P.,University of Toronto | Irving M.,Murdoch Childrens Research Institute | And 2 more authors.
Clinical Orthopaedics and Related Research | Year: 2011

Background: Abnormal development and growth of the capital femoral epiphysis and acetabulum are associated with a wide variety of underlying etiologies, one of which is Legg-Calvé-Perthes disease. Case Description: We report the cases of two children who presented with abnormal development of both hips and in whom novel mutations in the COL2A1 gene were found. These cases illustrate the importance of identifying individuals with a type II collagen abnormality, as it informs management, allows investigation for other complications, and provides the opportunity for accurate genetic counseling and consideration of other family members who might be at risk. Literature Review: The literature documents numerous private mutations in COL2A1 associated with diverse clinical phenotypes including bilateral hip dysplasia and premature osteoarthritis. Some of these mutations are associated with a joint-specific phenotype but few other skeletal or extraskeletal manifestations. Only careful clinical examination of children presenting with hip anomalies therefore will reveal additional findings that warrant an evaluation by a clinical geneticist. DNA mutation analysis may be useful for making a specific diagnosis and identifying other at-risk family members. Purposes and Clinical Relevance: The purpose of our report is to alert clinicians to the possibility that children who present with bilateral Perthes-like disease of the hip might have an underlying mutation in the gene encoding type II collagen. It is important to consider this in the differential diagnosis and workup of such children as it has specific prognostic, clinical, genetic counseling, and reproductive sequelae. © 2011 The Association of Bone and Joint Surgeons®. Source

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