Submission Details

ALK was first reported in relation to autosomal dominant neuroblastoma in 2008 (De Mosse et al. PMID: 18724359). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found only one disease entity, neuroblastoma, susceptibility to, 3 (MONDO:0013083), associated with this gene. ALK encodes the anaplastic lymphoma kinase. Multiple studies of case level have been performed with families segregating missense variants of ALK with neuroblastoma, with incomplete penetrance. Genetic evidence supporting this gene-disease relationship includes case-level data, and segregation data (8 points). 7 missense variants have been reported in 9 probands in 4 publications (PMIDs: 18724359, 18923525, 22071890, 21972109) are included in this curation. Variants in this gene segregated with disease in 8 additional family members (PMIDs: 18724359, 22071890). These families were detected with the germline pathogenic variants in the ALK gene, especially enriched in the tyrosine kinase domain. This gene-disease association is also supported by experimental evidence. (5.5 points, PMIDs: 18923524, 18923525, 22071890, 22764207). The pattern of disease in the ALK p.F1174L transgenic mice largely recapitulates the clinical spectrum of human neuroblastoma. In vitro also study showed that cells expressing ALK p.T1151M or p.R1275Q mutation were sensitive to the small-molecule inhibitor of ALK, TAE684, compared to untreated control, suggested mutant ALK protein showed increased kinase activity and resulting in the cell proliferation. This cell-based analysis further supports these two variants are gain of function variants. In summary, there is definitive evidence to support the relationship between ALK and autosomal dominant neuroblastoma. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.