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Cleft lip and/or palate (CL/P) are common structural birth defects in humans. We used exome sequencing to study a patient with bilateral CL/P and identified a single nucleotide deletion in the patient and her similarly affected son—c.546_546delG, predicting p.Gln183Arg fs *57 in the Distal-less 4 ( DLX4 ) gene. The sequence variant was absent from databases, predicted to be deleterious and was verified by Sanger sequencing. In mammals, there are three  Dlx  homeobox clusters with closely located gene pairs ( Dlx1 / Dlx2 ,  Dlx3 / Dlx4 ,  Dlx5 / Dlx6 ).  In situ  hybridization showed that  Dlx4  was expressed in the mesenchyme of the murine palatal shelves at E12.5, prior to palate closure. Wild-type human  DLX4 , but not mutant  DLX4 _c.546delG, could activate two murine  Dlx  conserved regulatory elements, implying that the mutation caused haploinsufficiency. We showed that reduced  DLX4  expression after short interfering RNA treatment in a human cell line resulted in significant up-regulation of  DLX3 ,  DLX5  and  DLX6 , with reduced expression of  DLX2  and significant up-regulation of  BMP4 , although the increased  BMP4  expression was demonstrated only in HeLa cells. We used antisense morpholino oligonucleotides to target the orthologous  Danio rerio  gene,  dlx4b , and found reduced cranial size and abnormal cartilaginous elements. We sequenced  DLX4  in 155 patients with non-syndromic CL/P and CP, but observed no sequence variants. From the published literature,  Dlx1 / Dlx2  double homozygous null mice and  Dlx5  homozygous null mice both have clefts of the secondary palate. This first finding of a  DLX4  mutation in a family with CL/P establishes  DLX4  as a potential cause of human clefts.

DLX4 is associated with orofacial clefting and abnormal jaw development