Title: Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion
Authors: Klopocki, Eva ×
Lohan, Silke
Doelken, Sandra C
Stricker, Sigmar
Ockeloen, Charlotte W
Soares Thiele de Aguiar, Renata
Lezirovitz, Karina
Mingroni Netto, Regina Celia
Jamsheer, Aleksander
Shah, Hitesh
Kurth, Ingo
Habenicht, Rolf
Warman, Matthew
Devriendt, Koenraad
Kordaß, Ulrike
Hempel, Maja
Rajab, Anna
Mäkitie, Outi
Naveed, Mohammed
Radhakrishna, Uppala
Antonarakis, Stylianos E
Horn, Denise
Mundlos, Stefan #
Issue Date: Feb-2012
Publisher: BMJ Publishing Group
Series Title: Journal of Medical Genetics vol:49 issue:2 pages:119-125
Abstract: BackgroundSplit-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.MethodsHigh 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.ResultsArray 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.ConclusionsGenomic 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.
ISSN: 0022-2593
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Klopocki.pdfpublisher's version pdf Published 636KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science