Supplementary Material for: Genome-Wide Linkage Analysis to Identify Genetic Modifiers of <i>ALK</i> Mutation Penetrance in Familial Neuroblastoma

<i>Background:</i> 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 <i>ALK</i> as the major familial NB gene. Dominant mutations in <i>ALK</i> 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 <i>ALK</i> mutations are affected by NB. <i>Methods:</i> To test whether genetic variation may explain the reduced penetrance of the disease phenotype, we analyzed genome-wide genotype data in <i>ALK</i> mutation-positive families using a model-based linkage approach with different liability classes for carriers and non-carriers of <i>ALK</i> mutations. <i>Results:</i> The region with the highest LOD score was located at chromosome 2p23–p24 and included the <i>ALK</i> locus under models of dominant and recessive inheritance. <i>Conclusions:</i> This finding suggests that variants in the non-mutated <i>ALK</i> gene or another gene linked to it may affect penetrance of the <i>ALK</i> mutations and risk of developing NB in familial cases.