Array-CGH analysis indicates a high prevalence of genomic rearrangements in holoprosencephaly: an updated map of candidate loci.
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.
Bendavid
Claude
C
Equipe Génétique des Pathologies Liées au Développement, UMR 6061 CNRS, IFR140 GFAS, Université de Rennes1, Rennes cedex, France.
Rochard
Lucie
L
Dubourg
Christèle
C
Seguin
Jonathan
J
Gicquel
Isabelle
I
Pasquier
Laurent
L
Vigneron
Jaqueline
J
Laquerrière
Annie
A
Marcorelles
Pascale
P
Jeanne-Pasquier
Corinne
C
Rouleau
Caroline
C
Jaillard
Sylvie
S
Mosser
Jean
J
Odent
Sylvie
S
David
Veronique
V
D002874:Chromosome Mapping; D015331:Cohort Studies; D017353:Gene Deletion; D015321:Gene Rearrangement; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D007621:Karyotyping; D009693:Nucleic Acid Hybridization; D017354:Point Mutation