title: A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation.
abstract: Synpolydactyly (SPD) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and an additional digit in the syndactylous web. In most cases SPD is caused by heterozygous mutations in HOXD13 resulting in the expansion of a N-terminal polyalanine tract. If homozygous, the mutation results in severe shortening of all metacarpals and phalanges with a morphological transformation of metacarpals to carpals. Here, we describe a novel homozygous missense mutation in a family with unaffected consanguineous parents and severe brachydactyly and metacarpal-to-carpal transformation in the affected child. We performed whole exome sequencing on the index patient, followed by Sanger sequencing of parents and patient to investigate cosegregation. The DNA-binding ability of the mutant protein was tested with electrophoretic mobility shift assays. We demonstrate that the c.938C>G (p.313T>R) mutation in the DNA-binding domain of HOXD13 prevents binding to DNA in vitro. Our results show to our knowledge for the first time that a missense mutation in HOXD13 underlies severe brachydactyly with metacarpal-to-carpal transformation. The mutation is non-penetrant in heterozygous carriers. In conjunction with the literature we propose the possibility that the metacarpal-to-carpal transformation results from a homozygous loss of functional HOXD13 protein in humans in combination with an accumulation of non-functional HOXD13 that might be able to interact with other transcription factors in the developing limb.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.|Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Ibrahim
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.|Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Naeimeh
authors.initials: N
authors.lastname: Tayebi
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Alexej
authors.initials: A
authors.lastname: Knaus
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Asita C
authors.initials: AC
authors.lastname: Stiege
authors.affiliation: Department of Genetic Welfare Organization, Kerman, Iran.
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Sahebzamani
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.|Berlin Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.|Max Planck Institute for Molecular Genetics, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany.|Berlin Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.|Max Planck Institute for Molecular Genetics, Berlin, Germany.|Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
mesh_terms: D000328:Adult; D001483:Base Sequence; D059327:Brachydactyly / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002348:Carpal Bones / Q000002:abnormalities / Q000378:metabolism; D002675:Child, Preschool; D003241:Consanguinity; D024202:Electrophoretic Mobility Shift Assay; D059472:Exome; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D050279:Metacarpal Bones / Q000002:abnormalities / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D013576:Syndactyly / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C513184:HOXD13 protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors
keywords: HOXD13; loss of function; synpolydactyly