Array-CGH analysis indicates a high prevalence of genomic rearrangements in holoprosencephaly: an updated map of candidate loci.

Claude Bendavid 1 Lucie Rochard 1 Christèle Dubourg 1, 2 Jonathan Seguin 1 Isabelle Gicquel 1 Laurent Pasquier 1, 3 Jaqueline Vigneron 4 Annie Laquerrière 5 Pascale Marcorelles 6 Corinne Jeanne-Pasquier 7 Caroline Rouleau 8 Sylvie Jaillard 9 Jean Mosser 1, 10 Sylvie Odent 1, 3 Véronique David 1, 2, *
* Auteur correspondant
1 IGDR - Institut de Génétique et Développement de Rennes
2 Service de biologie moléculaire
3 Service de génétique clinique
4 Consultation de Génétique
5 Néovasc - Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement
6 Service d'Anatomie Pathologique
7 Laboratoire d'anatomie pathologique
8 Laboratoire d'anatomie pathologique
9 Service de Cytogénétique et de Biologie Cellulaire
10 Plate-forme transcriptome
Abstract : Holoprosencephaly (HPE) is the most frequent malformation of the brain. To date, 12 different HPE loci and 8 HPE genes have been identified from recurrent chromosomal rearrangements or from the sequencing of genes from Nodal and SHH pathways. Our cohort of HPE patients presents a high genetic heterogeneity. Point mutations were found in SHH, ZIC2, SIX3, and TGIF genes in about 20% of cases (with 10% in SHH). Deletions in these same genes were found in 7.5% of the patients and 4.4% presented with other subtelomeric gain or losses. Consequently, the molecular basis of HPE remains unknown in 70% of our cohorts. To detect new HPE candidate genes, we used array-CGH to refine the previous karyotype based HPE loci map. We analyzed 111 HPE patients with high-performance Agilent oligonucleotidic arrays and found that 28 presented anomalies involving known or new potential HPE loci located on different chromosomes but with poor redundancy. This study showed an impressive rate of 19 patients among 111 with de novo chromosomal anomalies giving evidence that microrearrangements could be a major molecular mechanism in HPE. Additionally, this study opens new insights on HPE candidate genes identification giving an updated HPE candidate loci map.
Keywords : holoprosencephaly CGH array rearrangements candidate loci
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Human Mutation, Wiley, 2009, 30 (8), pp.1175-82. 〈10.1002/humu.21016〉
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Claude Bendavid, Lucie Rochard, Christèle Dubourg, Jonathan Seguin, Isabelle Gicquel, et al.. Array-CGH analysis indicates a high prevalence of genomic rearrangements in holoprosencephaly: an updated map of candidate loci.. Human Mutation, Wiley, 2009, 30 (8), pp.1175-82. 〈10.1002/humu.21016〉. 〈inserm-00404487〉

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