title: Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotype.
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.
authors.affiliation: Institute of Human Genetics, Charitè Universitätsmedizin, Berlin, Germany.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dutrannoy
authors.forename: Ilja
authors.initials: I
authors.lastname: Demuth
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Kateryna
authors.initials: K
authors.lastname: Konrat
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Janina
authors.initials: J
authors.lastname: Radszewski
authors.forename: Susanne
authors.initials: S
authors.lastname: Rothe
authors.forename: Mario T
authors.initials: MT
authors.lastname: Schellenberger
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Keng Wee
authors.initials: KW
authors.lastname: Teik
authors.forename: Revathy
authors.initials: R
authors.lastname: Nallusamy
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Karl
authors.initials: K
authors.lastname: Sperling
authors.forename: Martin
authors.initials: M
authors.lastname: Digweed
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle; D002648:Child; D002675:Child, Preschool; D043171:Chromosomal Instability / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D049932:Nijmegen Breakage Syndrome / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C508551:NHEJ1 protein, human; D045643:DNA Repair Enzymes