ClinVar

Description

The copy number loss of 7q21.3 involves three protein-coding genes, including DYNC1I1 (OMIM 603772), SLC25A13 (OMIM 603859), and SEM1 (OMIM 601285) and is expected to cause phenotypic and developmental abnormalities. Overlapping deletions of this region preserving candidate genes DLX5 and DLX6, have been reported in multiple familial patients with a variable phenotype including split hand foot malformation (SHFM), hearing loss, intellectual disability of variable degree, and significant craniofacial abnormalities (Ramos-Zaldivar et al. J Med Case Rep. 2016 Jun 13;10(1):156. PMID: 27291887; Delgado et al. Mol Cytogenet. 2015 Jun 13;8:37. PMID: 26075025; Tayebi et al. Orphanet J Rare Dis. 2014 Jul 29;9:108. PMID: 25231166). Reduced penetrance has also been reported (Rattanasopha et al. J Med Genet. 2014 Dec;51(12):817-23. PMID: 25332435). The minimal SHFM critical region (880 Kb), suggested by Delgado et al., is fully encompassed within the current deleted interval (Delgado S et al. Mol Cytogenet. 2015 Jun 13;8:37. PMID: 26075025). The enhancers of DLX5/6 within DYNC1I1, not the DLX5/6 gene locus, also fall within the current deleted interval. Loss of these enhancer elements has been suggested as one of the SHFM disease mechanisms (Birnbaum RY, et al. Hum Mol Genet. 2012 Nov 15;21(22):4930-8. PMID: 22914741). Rattanasopha et al. further suggested that paternal deletion of enhancers of the osteoblast-specific maternally imprinted DLX5/6 genes may result in absence of their proteins, thus may produce the disease phenotype. Additional information on this locus: Biallelic pathogenic sequence variants of SLC25A13 are associated with autosomal recessive conditions of citrullinemia (OMIM 603471 and OMIM 605814).