TY - JOUR T1 - Duplications of <em>BHLHA9</em> are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion JF - Journal of Medical Genetics JO - J Med Genet SP - 119 LP - 125 DO - 10.1136/jmedgenet-2011-100409 VL - 49 IS - 2 AU - Eva Klopocki AU - Silke Lohan AU - Sandra C Doelken AU - Sigmar Stricker AU - Charlotte W Ockeloen AU - Renata Soares Thiele de Aguiar AU - Karina Lezirovitz AU - Regina Celia Mingroni Netto AU - Aleksander Jamsheer AU - Hitesh Shah AU - Ingo Kurth AU - Rolf Habenicht AU - Matthew Warman AU - Koenraad Devriendt AU - Ulrike Kordaß AU - Maja Hempel AU - Anna Rajab AU - Outi Mäkitie AU - Mohammed Naveed AU - Uppala Radhakrishna AU - Stylianos E Antonarakis AU - Denise Horn AU - Stefan Mundlos Y1 - 2012/02/01 UR - http://jmg.bmj.com/content/49/2/119.abstract N2 - 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. ER -