title: An exploratory study of predisposing genetic factors for DiGeorge/velocardiofacial syndrome.
abstract: DiGeorge/velocardiofacial syndrome (DGS/VCFS) is a disorder caused by a 22q11.2 deletion mediated by non-allelic homologous recombination (NAHR) between low-copy repeats (LCRs). We have evaluated the role of LCR22 genomic architecture and PRDM9 variants as DGS/VCFS predisposing factors. We applied FISH using fosmid probes on chromatin fibers to analyze the number of tandem repeat blocks in LCR22 in two DGS/VCFS fathers-of-origin with proven 22q11.2 NAHR susceptibility. Results revealed copy number variations (CNVs) of L9 and K3 fosmids in these individuals compared to controls. The total number of L9 and K3 copies was also characterized using droplet digital PCR (ddPCR). Although we were unable to confirm variations, we detected an additional L9 amplicon corresponding to a pseudogene. Moreover, none of the eight DGS/VCFS parents-of-origin was heterozygote for the inv(22)(q11.2) haplotype. PRDM9 sequencing showed equivalent allelic distributions between DGS/VCFS parents-of-origin and controls, although a new PRDM9 allele (L50) was identified in one case. Our results support the hypothesis that LCR22s variations influences 22q11.2 NAHR events, however further studies are needed to confirm this association and clarify the contribution of pseudogenes and rare PDRM9 alleles to NAHR susceptibility.
authors.affiliation: Genetics of Male Fertility Group, Unitat de Biologia Cel·lular (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193-Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Vergés
authors.affiliation: Genetics of Male Fertility Group, Unitat de Biologia Cel·lular (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193-Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Vidal
authors.affiliation: Secció de Genètica Clínica. Hospital Universitari Sant Joan de Déu, 08950-Esplugues de Llobregat, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Geán
authors.affiliation: Laboratori de Genòmica de la Salut, Hospital Universitari Son Espases (HUSE), Palma de Mallorca, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Alemany-Schmidt
authors.affiliation: Laboratori de Genòmica de la Salut, Hospital Universitari Son Espases (HUSE), Palma de Mallorca, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Oliver-Bonet
authors.affiliation: Genetics of Male Fertility Group, Unitat de Biologia Cel·lular (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193-Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Blanco
mesh_terms: D056915:DNA Copy Number Variations; D004062:DiGeorge Syndrome / Q000235:genetics*; D005192:Family Health; D020022:Genetic Predisposition to Disease; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016133:Polymerase Chain Reaction; D012091:Repetitive Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human