title: Genome-wide linkage analysis to identify genetic modifiers of ALK mutation penetrance in familial neuroblastoma.
abstract: BACKGROUND
  Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50% of familial NB cases. However, in the families used for the linkage study, only about 50% of carriers of ALK mutations are affected by NB.
  
  
  METHODS
  To test whether genetic variation may explain the reduced penetrance of the disease phenotype, we analyzed genome-wide genotype data in ALK mutation-positive families using a model-based linkage approach with different liability classes for carriers and non-carriers of ALK mutations.
  
  
  RESULTS
  The region with the highest LOD score was located at chromosome 2p23-p24 and included the ALK locus under models of dominant and recessive inheritance.
  
  
  CONCLUSIONS
  This finding suggests that variants in the non-mutated ALK gene or another gene linked to it may affect penetrance of the ALK mutations and risk of developing NB in familial cases.
authors: Division of Genetics, The Children's Hospital of Philadelphia, Pa., USA. devoto @ chop.edu
authors: Marcella
authors: M
authors: Devoto
authors: Claudia
authors: C
authors: Specchia
authors: Marci
authors: M
authors: Laudenslager
authors: Luca
authors: L
authors: Longo
authors: Hakon
authors: H
authors: Hakonarson
authors: John
authors: J
authors: Maris
authors: Yael
authors: Y
authors: Mossé
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002648:Child; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases