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Expression pattern of Zdhhc8 is shown in the adult cerebellum (left) and the cortex (right). d Expression localization of Cdc45, Ranbp1, and Sept5 in the entire cortical hemisphere of E14.5 embryos (left) and in a higher magnification (right). c mRNA ( Prodh, Zdhhc8, Sept5, Gnb1l, Ranbp1, Dgcr8, Arvcf, Dgcr2, and Trmt2a) or protein (Ufd1l, Hira, Comt) expression of selected genes at mouse embryonic stage E10.5. b Protein-coding genes ( n = 56) are color-coded based on primary, putative, or family member functions as eleven groups. Low copy repeats (LCRs) are shown as gray boxes: LCR A-D (not to scale). The essential question remains: how CNVs of one, many, or all 22q11.2 genes disrupts developmental and homeostatic mechanisms and complicates the lives of children and adults with 22q11DS. Clearly, the range of genomic lesions, numbers of genes, and spectrum of phenotypes that define 22q11 CNV disorders defies straightforward explanations of genotype to phenotype correlations. In addition to these physical manifestations, 22q11.2 deletion syndrome (22q11DS) is associated with behavioral and psychiatric complications such as schizophrenia (SCZ) autistic spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorder, as well as intellectual and learning disabilities. Deleted individuals have complex and variable phenotypes including developmental delay, congenital heart defects, craniofacial anomalies such as cleft palate and retrognathia, musculoskeletal anomalies, eye anomalies, hearing loss, absent or small thymus and parathyroid glands, hypocalcemia, compromised immune system, feeding difficulties, and seizures. The smaller 1.5 Mb “minimal critical” deletion, occurs between LCR A and LCR B in ∼ 10% of affected individuals. More than 85% of recombination occurs between LCR A and LCR D resulting in a 3 Mb “typical” deletion.
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These LCRs, due to substantial sequence similarity, facilitate non-allelic homologous meiotic recombination, or “deletion by crossing over of repetitive DNA”, resulting in unbalanced translocation, deletions, or duplication.
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At least four repetitive DNA “cassettes” known as low copy-number repeats (LCRs): LCR A, B, C, and D define the region (Fig. The frequency of 22q11.2 deletion-the chromosomal/copy number variant (CNV) that results in most cases of DiGeorge/22q11DS -reflects the unusual genomic architecture of human chromosome 22 (hChr22), position q11.2. Subsequently, 22q11.2 deletion emerged as a major genomic lesion associated with vulnerability for several clinically defined behavioral deficits common to a number of neurodevelopmental disorders (Fernandez et al., Principles of Developmental Genetics, 2015 Robin and Shprintzen, J Pediatr 147:90-6, 2005 Schneider et al., Am J Psychiatry 171:627-39, 2014). This disorder was known as DiGeorge syndrome, Velo-cardio-facial syndrome (VCFS) or conotruncal anomaly face syndrome (CTAF) based upon diagnostic cardiovascular, pharyngeal, and craniofacial anomalies (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011 Burn et al., J Med Genet 30:822-4, 1993) before this phenotypic spectrum was associated with 22q11.2 CNVs. 22q11.2 deletion syndrome (22q11DS), a copy number variation (CNV) disorder, occurs in approximately 1:4000 live births due to a heterozygous microdeletion at position 11.2 (proximal) on the q arm of human chromosome 22 (hChr22) (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011).