Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome‐like phenotype |
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| Authors: | Véronique Dutrannoy Ilja Demuth Ulrich Baumann Detlev Schindler Kateryna Konrat Heidemarie Neitzel Gabriele Gillessen‐Kaesbach Janina Radszewski Susanne Rothe Mario T Schellenberger Gudrun Nürnberg Peter Nürnberg Keng Wee Teik Revathy Nallusamy André Reis Karl Sperling Martin Digweed Raymonda Varon |
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| Institution: | 1. Institute of Human Genetics, Charitè Universit?tsmedizin, Berlin, Germany;2. Department of Pediatric Pulmonology and Neonatology, Medical School Hannover, Hannover, Germany;3. Department of Human Genetics, University of Würzburg, Würzburg, Germany;4. Institute of Human Genetics, Universit?t zu Lübeck;5. Lübeck, Germany;6. Cologne Center for Genomics and Institute for Genetics, University of Cologne, Cologne, Germany;7. Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD), University of Cologne, Cologne, Germany;8. Hospital Pulau Pinang, Jalan Residensi, Malaysia;9. Institute of Human Genetics, University Hospital Erlangen, Friedrich–Alexander University Erlangen–Nuremberg, Erlangen, Germany |
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| Abstract: | We have previously shown that mutations in the genes encoding DNA Ligase IV (LIGIV) and RAD50, involved in DNA repair by nonhomologous‐end joining (NHEJ) and homologous recombination, respectively, lead to clinical and cellular features similar to those of Nijmegen Breakage Syndrome (NBS). Very recently, a new member of the NHEJ repair pathway, NHEJ1, was discovered, and mutations in patients with features resembling NBS were described. Here we report on five patients from four families of different ethnic origin with the NBS‐like phenotype. Sequence analysis of the NHEJ1 gene in a patient of Spanish and in a patient of Turkish origin identified homozygous, previously reported mutations, c.168C>G (p.Arg57Gly) and c.532C>T (p.Arg178Ter), respectively. Two novel, paternally inherited truncating mutations, c.495dupA (p.Asp166ArgfsTer20) and c.526C>T (p.Arg176Ter) and two novel, maternal genomic deletions of 1.9 and 6.9 kb of the NHEJ1 gene, were found in a compound heterozygous state in two siblings of German origin and in one Malaysian patient, respectively. Our findings confirm that patients with NBS‐like phenotypes may have mutations in the NHEJ1 gene including multiexon deletions, and show that considerable clinical variability could be observed even within the same family. Hum Mutat 31:1059–1068, 2010. © 2010 Wiley‐Liss, Inc. |
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| Keywords: | Nijmegen Breakage Syndrome‐like NBS microcephaly NHEJ1 gene clinical variability |
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