Clinical Variability and Novel Mutations in the NHEJ1 Gene in Patients with a Nijmegen Breakage Syndrome-like Phenotype

Raymonda Varon (1) , Véronique Dutrannoy (2) , Ilja Demuth (2) , Kateryna Konrat (2) , Heidemarie Neitzel (2) , Janina Radszewski (2) , Susanne Rothe (2) , Karl Sperling (2) , Martin Digweed (2) , Ulrich Baumann (3) , Detlev Schindler (4) , Gabriele Gillessen-Kaesbach (5) , Mario T Schellenberger (2) , Wee Teik Keng (6) , Revathy Nallusamy (6) , André Reis (7) , Gudrun Nürnberg (8) , Peter Nürnberg (9, 10)

1 Institute of Human Genetics
2 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
3 Department of Pediatric Pulmonology and Neonatology
4 Department of Human Genetics
5 Institute of Human Genetics
6 Hospital Pulau Pinang
7 Institute of Human Genetics [Erlangen, Allemagne]
8 Cologne Center for Genomics
9 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)
10 Cologne Center for Genomics and Institute for Genetics

We have previously shown that mutations in the genes encoding DNA Ligase IV (LIGIV) and RAD50, involved in DNA repair by non-homologous-end joining (NHEJ), 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 5 patients from 4 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.Arg178X), respectively. Two novel, paternally inherited truncating mutations, c.495dupA (p.Asp166ArgfsX20) and c.526C>T (p.Arg176X) 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 multi-exon deletions and show that considerable clinical variability could be observed even within the same family.

Mots clés: Life Sciences

Raymonda Varon, Véronique Dutrannoy, Ilja Demuth, Kateryna Konrat, Heidemarie Neitzel, et al.. Clinical Variability and Novel Mutations in the NHEJ1 Gene in Patients with a Nijmegen Breakage Syndrome-like Phenotype. Human Mutation, 2010, 31 (9), pp.1059. ⟨10.1002/humu.21315⟩. ⟨hal-00556036⟩