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Whole exome sequencing identifies FGF16 nonsense mutations as the cause of X-linked recessive metacarpal 4/5 fusion
  1. Aleksander Jamsheer1,2,
  2. Tomasz Zemojtel3,4,
  3. Mateusz Kolanczyk3,5,
  4. Sigmar Stricker5,
  5. Jochen Hecht5,6,
  6. Peter Krawitz3,
  7. Sandra C Doelken3,
  8. Renata Glazar2,
  9. Magdalena Socha1,
  10. Stefan Mundlos3,5,6
  1. 1Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland
  2. 2NZOZ Center for Medical Genetics GENESIS, Poznan, Poland
  3. 3Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany
  4. 4Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
  5. 5Max Planck Institute for Molecular Genetics, Berlin, Germany
  6. 6Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany
  1. Correspondence to Dr Aleksander Jamsheer, Department of Medical Genetics, Poznan University of Medical Sciences, Grunwaldzka 55 Street, pav. 15, Poznan 60-352, Poland; jamsheer{at} and Professor Stefan Mundlos, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany; stefan.mundlos{at}


Background Metacarpal 4–5 fusion (MF4; MIM %309630) is a rare congenital malformation of the hand characterised by the partial or complete fusion of the fourth and fifth metacarpals. The anomaly occurs as an isolated trait or part of a genetic syndrome.

Methods To search for disease-causing mutation, whole exome sequencing (WES) was performed on samples from a single trio. Before WES, molecular screening including gene sequencing and array comparative genomic hybridisation was applied. Validation of WES and segregation studies were done using routine Sanger sequencing.

Results Exome sequencing detected a nonsense mutation (c.C535T; p.R179X) in exon 3 of the FGF16 gene, which maps to chromosome Xq21.1. Mutational screening of the FGF16 gene performed in an unrelated proband of different ethnicity showed another nonsense mutation in exon 3 (c.C470A; p.S157X).

Conclusions This study shows that truncating mutations of FGF16 are associated with X-linked recessive metacarpal 4–5 fusion. The study provides evidence for the involvement of FGF16 in the fine tuning of the human skeleton of the hand.

  • metacarpal 4-5 fusion
  • metacarpal synostosis
  • X-linked inheritance
  • FGF16
  • nonsense mutation

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