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  Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion

Klopocki, E., Lohan, S., Doelken, S. C., Stricker, S., Ockeloen, C. W., Soares Thiele de Aguiar, R., et al. (2012). Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. Journal of Medical Genetics (London), 49(2), 119-125. doi:10.1136/jmedgenet-2011-100409.

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© 2012 by the BMJ Publishing Group Ltd




Klopocki, E.1, 2, Author              
Lohan, S.1, 2, Author
Doelken, S. C., Author
Stricker, S.1, Author              
Ockeloen, C. W., Author
Soares Thiele de Aguiar, R., Author
Lezirovitz, K., Author
Netto, Mingroni, Author
Jamsheer, A., Author
Shah, H., Author
Kurth, I., Author
Habenicht, R., Author
Warman, M., Author
Devriendt, K., Author
Kordass, U., Author
Hempel, M., Author
Rajab, A., Author
Makitie, O., Author
Naveed, M., Author
Radhakrishna, U., Author
Antonarakis, S. E., Author              Horn, D.3, Author              Mundlos, S.1, 2, Author               more..
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1433557              
2Institute for Medical Genetics and Human Genetics, Charité—Universitätsmedizin Berlin, Berlin, Germany, ou_persistent22              
3AG Deussing, Jan, Florian Holsboer (Direktor), Max Planck Institute of Psychiatry, Max Planck Society, München, Germany, ou_1607145              


Free keywords: Animals Basic Helix-Loop-Helix Transcription Factors/ genetics Ectromelia/ genetics Female Fingers/abnormalities Gene Duplication Gene Knockdown Techniques Genetic Association Studies Genotype Hand Deformities, Congenital/ genetics Humans Inheritance Patterns Limb Deformities, Congenital/genetics Male Pedigree Phenotype Tibia/ abnormalities Zebrafish/embryology/genetics
 Abstract: BACKGROUND: Split-hand/foot malformation (SHFM)-also known as ectrodactyly-is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1-6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved. METHODS: High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments. RESULTS: Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ~11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins. CONCLUSIONS: Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of non-penetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.


Language(s): eng - English
 Dates: 2012-02
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1136/jmedgenet-2011-100409
 Degree: -



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Title: Journal of Medical Genetics (London)
  Other : J Med Genet
Source Genre: Journal
Publ. Info: London : British Medical Association
Pages: - Volume / Issue: 49 (2) Sequence Number: - Start / End Page: 119 - 125 Identifier: ISSN: 0022-2593
CoNE: https://pure.mpg.de/cone/journals/resource/954925415940