Consequences of 22q11.2 Microdeletion on the Genome, Individual and Population Levels

Abstract

Chromosomal 22q11.2 deletion syndrome (22q11.2DS) (ORPHA: 567) caused by microdeletion in chromosome 22 is the most common chromosomal microdeletion disorder in humans. Despite the same change on the genome level, like in the case of monozygotic twins, phenotypes are expressed differently in 22q11.2 deletion individuals. The rest of the genome, as well as epigenome and environmental factors, are not without influence on the variability of phenotypes. The penetrance seems to be more genotype specific than deleted locus specific. The transcript levels of deleted genes are not usually reduced by 50% as assumed due to haploinsufficiency. 22q11.2DS is often an undiagnosed condition, as each patient may have a different set out of 180 possible clinical manifestations. Diverse dysmorphic traits are present in patients from different ethnicities, which makes diagnosis even more difficult. 22q11.2 deletion syndrome serves as an example of a genetic syndrome that is not easy to manage at all stages: diagnosis, consulting and dealing with.

Different Types of Deletions Created by Low-Copy Repeats Sequences Location in 22q11.2 Deletion Syndrome: Genotype–Phenotype Correlation

“…The latest studies suggest that cardiovascular anomalies are present in 49–83% of people with 22q11.2DS [ 4 , 30 ]; the most common are septal defects (23%), followed by tetralogy of Fallot (18%) [ 5 ]. In our patients, the prevalence of cardiac defects was 71.1% and a higher occurrence of Fallot tetralogy was observed—45.2% out of the patients with heart defects.…”

Chromosome 22q11.2 Deletion Syndrome: A Comprehensive Review of Molecular Genetics in the Context of Multidisciplinary Cinical Approach

“…The chromosomal 22q11.2 DS is a clinically highly variable microdeletion syndrome with differently expressed phenotypes, with wide interfamilial and intrafamilial variability in patients sharing the same genetic underpinnings [118]. This is due to both the remarkable complexity of the 22q11.2 region with LCR blocks and the high susceptibility of this region to meiotic errors as well as the epigenomic and environmental factors influencing the phenotypic variability [119]. Based on functional genomic assessments, it has also been hypothesized that theories on single-gene haploinsufficiency in 22q11.2 DS can not be supported.…”

Central 22q11.2 deletion (LCR22 B‐D) in a fetus with severe fetal growth restriction and a mother with severe systemic lupus erythematosus: Further evidence of CRKL haploinsufficiency in the pathogenesis of 22q11.2 deletion syndrome

“…These patients present with varying penetrance and a broad phenotypic spectrum including dysmorphic features, congenital heart disease (CHD), hypoplastic thymus and Tcell deficiency, and hypocalcemia. Prenatal findings detectable by ultrasound include cardiac defects, thymic hypoplasia or aplasia, fetal growth restriction (FGR), renal and urinary abnormalities, increased nuchal translucency thickness, and abnormal amniotic fluid levels (Chen & Chien, 2008 1S) (Burnside, 2015;Karbarz, 2020). 22q11.2 DS is usually diagnosed via classical fluorescence in situ hybridization (FISH) with TUPLE1 (HIRA) probe or chromosomal microarray analysis (CMA).…”

“…Nested deletions occur at a lower frequency; 8–10% have a nested proximal LCR22A‐B (1.5 Mb) or LCR 22A‐C (2.0 Mb) deletion, and 4–5% have central LCR22B‐D (1.5 Mb) and LCR22C‐D (0.7 Mb) deletions. Other deletions include distal deletions such as distal type I LCR22C‐E (1.8 Mb), LCR22D‐E (1.1 Mb) and LCR22D‐F (1.8 Mb) deletions (Figure 1S) (Burnside, 2015; Karbarz, 2020). 22q11.2 DS is usually diagnosed via classical fluorescence in situ hybridization (FISH) with TUPLE1 (HIRA) probe or chromosomal microarray analysis (CMA).…”

“…Deleted region in our patients (yellow box) is flanked by LCR22B–LCR22D. Typical deletion, proximal nested deletions, central deletions, and distal type I deletions are depicted with deletion size and prevalence data from Karbarz (2020).…”