ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 10q24.32
  • GRCh37/hg19 chr10: 103,370,421-103,455,052
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr10: 101,610,664-101,695,295
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000010.10) (NC_000010.11)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

PMID: 12913067 De Mollerat (2003): This is a report of 7 patients with SHFM3 (split hand/foot malformation 3) who all had a tandem duplication which included LBX1, BTRC, and POLL, and had a breakpoint within FBXW4 (DAC), potentially disrupting this gene. PMID: 23596994 Dai (2013): A report of a four-generation Chinese family with SHFM3 that co-segregates with a discontinuous duplication of the 10q24 region which includes a portion of FBXW4. Also of note, in 2013, Vergult et al. (PMID: 22995989) reported an 80.2 kb deletion involving only FBXW4 in a European individual with a radial ray defect. This deletion was inherited from a reportedly phenotypically normal mother. No sequence variants were found in FBXW4 on the other chromosome. This group then sequenced the coding regions and 6 conserved non-coding elements of the gene in a larger cohort of 54 European individuals with radial ray defects. They detected a g.103380009A>G variant in an individual with bilateral radial dysplasia for whom no parental samples were available. This variant was not detected in 96 ethnicity-matched controls or in the 1000 Genomes cohort. No functional studies were performed. Based on this evidence alone, it is unclear whether haploinsufficiency of FBXW4 plays a role in radial ray defects.

Triplosensitivity phenotype comment:

Tandem duplications at 10q24 are associated with split hand/foot malformation 3 (SHFM3) syndrome: PMID: 16235095 Kano (2005): This report includes 2 patients with SHFM3 who had similar duplications. One duplication including all of BTRC, POLL, and DPCD, and had a breakpoint within FBXW4 (DAC). The other duplication extended distally to encompass all of FBXW4. PMID: 19584065 Dimitrov (2010): This paper includes 6 patients with both syndromic and non-syndromic SHFM3 who have duplications at 10q24 of varying size, which include FBXW4. They comment on genotype-phenotype correlations. PMID: 21485001 Filho (2011): A report of two brothers with syndromic SHFM3 who have 10q24 duplications that include all of FBXW4. Their mother was found to have somatic mosaicism for this duplication.