Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/17287
Title: Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.
Authors: Knaus, Alexej;Pantel, Jean Tori;Pendziwiat, Manuela;Hajjir, Nurulhuda;Zhao, Max;Hsieh, Tzung-Chien;Schubach, Max;Gurovich, Yaron;Fleischer, Nicole;Jäger, Marten;Köhler, Sebastian;Muhle, Hiltrud;Korff, Christian;Møller, Rikke S;Bayat, Allan;Calvas, Patrick;Chassaing, Nicolas;Warren, Hannah;Skinner, Steven;Louie, Raymond;Evers, Christina;Bohn, Marc;Christen, Hans-Jürgen;van den Born, Myrthe;Obersztyn, Ewa;Charzewska, Agnieszka;Endziniene, Milda;Kortüm, Fanny;Brown, Natasha;Robinson, Peter N;Schelhaas, Helenius J;Weber, Yvonne;Helbig, Ingo;Mundlos, Stefan;Horn, Denise;Krawitz, Peter M
Affiliation: Institut für Medizinische Genetik und Humangenetik, Charité Universitätsmedizin Berlin, 13353, Berlin, Germany
Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany
Berlin-Brandenburg School for Regenerative Therapies, Charité Universitätsmedizin Berlin, 13353, Berlin, Germany
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127, Bonn, Germany
Department of Neuropediatrics, University Medical Center Schleswig Holstein, 24105, Kiel, Germany
Berlin Institute of Health (BIH), 10178, Berlin, Germany
FDNA Inc., Boston, MA, USA
Unité de Neuropédiatrie, Université de Genève, CH-1211, Genève, Switzerland
Danish Epilepsy Centre, DK-4293, Dianalund, Denmark
Institute for Regional Health Services Research, University of Southern Denmark, DK-5000, Odense, Denmark
Department of Pediatrics, University Hospital of Hvidovre, 2650, Hvicovre, Denmark
Service de Génétique Médicale, Hôpital Purpan, CHU, 31059, Toulouse, France
Greenwood Genetic Center, SC29646, Greenwood, USA
Genetische Poliklinik, Universitätsklinik Heidelberg, 69120, Heidelberg, Germany
St. Bernward Krankenhaus, 31134, Hildesheim, Germany
Kinderkrankenhaus auf der Bult, Hannoversche Kinderheilanstalt, 30173, Hannover, Germany
Department for Clinical Genetics, Erasmus MC, 3000, Rotterdam, Netherlands
Institute of Mother and Child Department of Molecular Genetics, 01-211, Warsaw, Poland
Neurology Department, Lithuanian University of Health Sciences, 50009, Kaunas, Lithuania
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
Victorian Clinical Genetics Services, Royal Children's Hospital, MCRI, Parkville, Australia
Department of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia
The Jackson Laboratory for Genomic Medicine, 06032, Farmington, USA
Departement of Neurology, Academic Center for Epileptology, 5590, Heeze, The Netherlands
Department of Neurology and Epileptology and Hertie Institute for Clinical Brain Research, University Tübingen, 72076, Tübingen, Germany
Pediatric Neurology, Children's Hospital of Philadelphia, 3401, Philadelphia, USA
Issue Date: 9-Jan-2018
EDate: 2018-01-09
Citation: Genome medicine 2018; 10(1): 3
Abstract: Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification. We studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals. We found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD. Due to the overlapping clinical spectrum of both HPMRS and MCAHS in the majority of affected individuals, the elevation of AP and the reduced surface levels of GPI-linked markers in both groups, a common classification as GPIBDs is recommended. The effectiveness of computer-assisted gestalt analysis for the correct gene inference in a GPIBD and probably beyond is remarkable and illustrates how the information contained in human faces is pivotal in the delineation of genetic entities.
URI: http://ahro.austin.org.au/austinjspui/handle/1/17287
DOI: 10.1186/s13073-017-0510-5
PubMed URL: 29310717
Type: Journal Article
Subjects: Anchor biosynthesis defects
Automated image analysis
GPI
Gene
Prediction
Appears in Collections:Journal articles

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