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.

Inversion polymorphism in a complete human genome assembly

“…This includes a large inversion polymorphism encompassing one of the most common rearrangements associated with autism at chromosome 16p11.2 and one of the most frequent deletions in the human population at the DiGeorge/VCF syndrome critical region (Additional file 1 : Fig. S18) [ 20 , 21 ]. We further investigate the Cooper syndrome region on chromosome 15q25.2 using available HPRC assemblies and define eight structurally diverse haplotypes with various frequencies in human populations.…”

Inversion polymorphism in a complete human genome assembly

“…Interestingly, all but one of these rare inversion polymorphisms overlap a pathogenic copy number variant in the human population, strengthening our recent observation of disease association (Porubsky, Höps, et al 2022). This includes a large inversion polymorphism encompassing one of the most common rearrangements associated with autism at chromosome 16p11.2, which maps to the DiGeorge/VCF syndrome critical region interval that has been extensively studied (Gebhardt et al 2003; Vergés et al 2017) and a multi-Mbp inversion corresponding to the Cooper syndrome region on chromosome 15q25.2. Using the HPRC assemblies ( Data availability ), we define eight structurally diverse haplotypes with various frequencies in human populations ( Fig.…”

Consideration of the haplotype diversity at nonallelic homologous recombination hotspots improves the precision of rearrangement breakpoint identification

“…Table S31 and S32). It is reasonable to assume that features present in addition to PRDM9‐binding sites, such as structural variants (CNVs) of the recombining paralogs or chromatin accessibility, can also influence NAHR frequency (Antonacci et al., ; Carvalho & Lupski, ; Cuscó et al., ; Vergés, Molina, Geán, Vidal, & Blanco, , ). Polymorphic large inversions present in the transmitting parents have been identified that predispose to NAHR‐mediated rearrangements involving a number of different human genes (Antonacci et al., ; Bayés, Magano, Rivera, Flores, & Pérez Jurado, ; Gimelli et al., ; Hobart et al., ; Koolen et al., ; Molina, Anton, Vidal, & Blanco, ; Osborne et al., ; Scherer et al., ; Sharp et al., ; Small, Iber, & Warren, ; Visser et al., ).…”