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Genetics of Holoprosencephaly (HPE), a congenital malformation of the developing human forebrain, is due to multiple genetic defects. Most genes that have been implicated in HPE belong to the sonic hedgehog signaling pathway. Here we describe a new candidate gene isolated from array comparative genomic hybridization redundant 6qter deletions, DELTA Like 1 (DLL1), which is a ligand of NOTCH. We show that DLL1 is co-expressed in the developing chick forebrain with Fgf8. By treating chick embryos with a pharmacological inhibitor, we demonstrate that DLL1 interacts with FGF signaling pathway. Moreover, a mutation analysis of DLL1 in HPE patients revealed a three-nucleotide deletion. These various findings implicate DLL1 in early patterning of the forebrain and identify NOTCH as a new signaling pathway involved in HPE.

Original publication




Journal article


Hum Mol Genet

Publication Date





1122 - 1131


Adult, Amino Acid Sequence, Androstenediols, Animals, Base Sequence, Chick Embryo, Female, Holoprosencephaly, Humans, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Molecular Sequence Data, Receptors, Notch, Sequence Alignment, Sequence Deletion, Signal Transduction