ClinVar Genomic variation as it relates to human health

Deletions of this region have been reported in multiple patients with a variable phenotype including split hand foot malformation (SHFM), hearing loss, intellectual disability of variable degree, and significant craniofacial abnormalities. Several candidate genes have been proposed including: DYNC1I1 and PPP1R9A (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; Rattanasopha et al. J Med Genet. 2014 Dec;51(12):817-23. PMID: 25332435). Some cases of split-hand/foot malformation-1 (SHFM1, OMIM 183600) represent a contiguous gene syndrome caused by deletion, duplication, or rearrangement of chromosome 7q21.3 involving the DSS1 (601285), DLX5 (600028), and DLX6 (600030) genes and possible regulatory elements in the region. Evidence exists that SHFM1 can also be caused by heterozygous mutation in the DLX5 gene. SHFM is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients with SHFM type 1 have been found to have intellectual disability, ectodermal and craniofacial findings, orofacial clefting, and hearing loss. Van Silfhout et al. reported three patients with SHFM1; two patients had a deletion and the third had an inversion, all involving chromosome 7q21q22. The authors concluded that the SHFM1 phenotype is most likely due to the simultaneously reduced expression of DLX5 and DLX6 (van Silfhout et al., Eur J Hum Genet. 2009 Nov;17(11):1432-8. PMID: 19401716). The copy number loss also involves SGCE; haploinsufficiency of which causes autosomal dominan tMyoclonus-dystonia (OMIM 159900). This is a movement disorderwhich onsets in childhood or adolescence and most often affects the neck, trunk, and upper limbs with less common involvement of the legs. Symptoms usually plateau in adulthood. In general, imprinting plays a role in this disorder given maternally derived SGCE alleles are not expressed and paternally derived SGCE alleles are expressed. Thus, almost all children who inherit an SGCE pathogenic variant from their fathers develop symptoms, whereas close to 95% of children who inherit an SGCE pathogenic variant from their mother do not (Raymond D. GeneReviews. [updated 2012 Jan 26]. PMID: 20301587). Additionally, patients with contiguous gene deletions that encompass SGCE and other genes may have additional clinical issues such as short stature, joint laxity and microcephaly (Peall et al. J Neurol. 2014 Dec;261(12):2296-304. PMID: 25209853).