ClinGen Dosage Sensitivity Curation Page

2p24.3 MYCN-DDX1 duplication region

  • Curation Status: Complete
  • id: ISCA-46287
  • Date last evaluated: 2017-08-07
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score:
  • ClinGen Triplosensitivity Score: 2


Location Information

Select assembly: (NC_000002.11) ()
  • Haploinsufficiency score:
  • Strength of Evidence (disclaimer): unknown

Haploinsufficiency phenotype comments:

This review pertains to the recurrent duplication of MYCN-DDX1. Please see the linked review for haploinsufficiency scoring of the gene MYCN.

  • Triplosensitivity score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
  • Triplosensitivity Phenotype: OrphaNet: 635
Evidence for gain of function phenotype
PubMed ID Description
27794475 Micale et al. (2016) describe a 13-month old boy with a 560 kb duplication at 2p24.3, involving the NBAS, DDX1, MYCNOS, and MYCN genes. His clinical features included hydrocephaly, ventricular septal defect, partial agenesis of the corpus callosum, and bilateral Wilms tumor. His mother was found to carry the same duplication with no clinical presentation suggesting incomplete penetrance.
24161495 Fievet et al. (2013) describe a 3-year-old girl and her father with a 569 kb duplication at 2p24.3, involving the NBAS, DDX1, MYCNOS, and MYCN genes. Both individuals presented with nephroblastoma, with the girl presenting prenatally with bilateral nephroblastomatosis. Both individuals also carried a chromosome 8 pericentric inversion; however, the authors were unable to establish a link between this finding and the renal tumors.
23401364 Van Mater et al. (2013) describe an 11-month old boy with a 1 Mb duplication at 2p24.3, involving the MYCN, MYCNOS,and DDX1 genes (partially including the FAM49A gene). His clinical features include high forehead, hypertelorism, postaxial polydactyly, and developmental delay. He developed Stage 4 neuroblastoma by 11 months of age. This duplication was de novo.

Triplosensitivity phenotype comment:

This review pertains to duplications that include both MYCN and DDX1 genes. Duplication of this region is associated with an increased risk for development of tumors, especially renal tumors and neuroblastoma. In addition, some patients have been reported with developmental phenotypes. At least two cases of inherited 2p24.3 (MYCN-DDX1 region) duplications are reported, and in one case, the parent was unaffected. Due to clinical variability and the limited number of patients with constitutionally-confirmed duplications in the literature, this region is currently scored as a 2. Genomic coordinates for this region were determined by using the smallest region of overlap for duplications reported in the literature (see Fievet et al., 2013 and Van Mater et al., 2013).