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

Xue Wang, Qian Xin, Lin Li, Jiangxia Li, Changwu Zhang, Rongfang Qiu, Chenmin Qian, Hailing Zhao, Yongchao Liu, Shan Shan, Jie Dang, Xianli Bian, Changshun Shao, Yaoqin Gong, Qiji Liu

Journal: European journal of human genetics : EJHG 2015;22(9):1105-10

PMID: 24496061

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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.558G>T (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.

Address: Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Medical Genetics, Shandong University School of Medicine, Jinan, China.; Department of Medical Genetics, Linyi People's Hospital, Linyi, China.; Department of Orthopedics, Cangshan People's Hospital, Cangshan, China.; Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

DOI: 10.1038/ejhg.2014.7

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MeSH Terms: Adult, Amino Acid Sequence, Child, Exome, Female, Foot Deformities, Congenital, Genes, Dominant, HEK293 Cells, Hand Deformities, Congenital, HeLa Cells, Hearing Loss, Sensorineural, Heterozygote, Homeodomain Proteins, Humans, Male, Molecular Sequence Data, Mutation, Missense, Pedigree, Transcription Factors