Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation

Abstract

Split-hand/foot malformation (SHFM) is a congenital limb deformity due to the absence or dysplasia of central rays of the autopod. Six SHFM loci have already been identified. Here we describe a Chinese family with autosomal-dominant SHFM1 that has previously been mapped to 7q21.2-21.3. The two affected family members, mother and son, showed deep median clefts between toes, ectrodactyly and syndactyly; the mother also showed triphalangeal thumbs. Exome sequencing and variant screening of candidate genes in the six loci known to be responsible for SHFM revealed a novel heterozygous mutation, c.558G4T (p. (Gln186His)), in distal-less homeobox 5 (DLX5). As DLX5 encodes a transcription factor capable of transactivating MYC, we also tested whether the mutation could affect DLX5 transcription acitivity. Results from luciferase reporter assay revealed that a mutation in DLX5 compromised its transcriptional activity. This is the first report of a mutation in DLX5 leading to autosomal-dominant SHFM1.

Dlx5 Homeodomain:DNA Complex: Structure, Binding and Effect of Mutations Related to Split Hand and Foot Malformation Syndrome

“…DLX genes encode homeodomain transcription factors that are primarily expressed during early embryogenesis [2] and regulate intercellular signaling across the interface between the neural and non-neural ectoderm, which is critical for inducing and patterning adjacent cell fates [6]. DLX5 is expressed in the median plane of the Apical Ectodermal Ridge (AER), which is essential for the establishment of the correct limb polarity and its development in the proximo-distal direction, along with the formation of digits [7, 8]. In humans, the six DLX genes are linked and convergently transcribed as gene pairs ( DLX1 and DLX2 , DLX5 and DLX6 , and DLX3 and DLX7 ) that share regulatory elements and expression patterns [9, 10].…”

Absent expression of the osteoblast-specific maternally imprinted genes,DLX5andDLX6,causes split hand/split foot malformation type I

“…10 The second family had two affected members, a mother and her son, with split feet and triphalangeal thumbs. Both had a heterozygous missense mutation in DLX5 , c.G558T (p.Q186H) 11. All other patients associated with the SHFM1 locus were caused by deletions or complex chromosomal rearrangements.…”

A Novel Heterozygous Intragenic Sequence Variant in DLX6 Probably Underlies First Case of Autosomal Dominant Split-Hand/Foot Malformation Type 1

“…Previously, chromosomal aberrations including deletions, duplications, translocations, and inversions in 7q21.2q21.3 encompassing DLX5 , DLX6 , and DYNC1I1 have been reported in families segregating SHFM1 in an autosomal dominant pattern. Three intragenic heterozygous mutations (p.Gln186His, p.Glu39 * , and p.Ala163-Profs * 55) in the DLX5 gene causing the autosomal dominant form of SHFM1 [Sowińska-Seidler et al, 2014;Wang et al, 2014;Ullah et al, 2016] and a homozygous missense variant (p.Gln178Pro) in the same gene causing the autosomal recessive form of SHFM1 have been reported [Shamseldin et al, 2012] ( Table 1 , 2 ) . Lango et al [2014] reported that disruption of exon 15 and 17 of the DYNC1I1 gene, enhancers of DLX5/6 , caused the autosomal dominant form of SHFM1 in humans .…”