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

Abstract

The 22q11.2 deletion syndrome is a multisystemic disorder characterized by a marked variability of phenotypic features, making the diagnosis challenging for clinicians. The wide spectrum of clinical manifestations includes congenital heart defects—most frequently conotruncal cardiac anomalies—thymic hypoplasia and predominating cellular immune deficiency, laryngeal developmental defects, midline anomalies with cleft palate and velar insufficiency, structural airway defects, facial dysmorphism, parathyroid and thyroid gland hormonal dysfunctions, speech delay, developmental delay, and neurocognitive and psychiatric disorders. Significant progress has been made in understanding the complex molecular genetic etiology of 22q11.2 deletion syndrome underpinning the heterogeneity of clinical manifestations. The deletion is caused by chromosomal rearrangements in meiosis and is mediated by non-allelic homologous recombination events between low copy repeats or segmental duplications in the 22q11.2 region. A range of genetic modifiers and environmental factors, as well as the impact of hemizygosity on the remaining allele, contribute to the intricate genotype-phenotype relationships. This comprehensive review has been aimed at highlighting the molecular genetic background of 22q11.2 deletion syndrome in correlation with a clinical multidisciplinary approach.

Rare and Complex Cardiac Anomalies Associated with 22q11.2 Deletion: An Ultrasonographic Visual Trip from Diagnosis until Delivery

“…The deletion is caused by chromosomal rearrangements in meiosis and is mediated by non-allelic homologous recombination events between low copy repeats or segmental duplications in the 22q11.2 region. A range of genetic modifiers and environmental factors, as well as the impact of hemizygosity on the remaining allele contribute to the intricate genotype-phenotype relationships [10].…”

“…For couples with no history of 22q11.2 microdeletion diagnosis in either parent, there are several possible routes to prenatal diagnostic testing that could identify a fetus with 22q11.2DS [8]. Although the diagnosis of this microdeletion has been traditionally based on the recognition of clinical features and cytogenetic testing using the fluorescence in situ hybridization (FISH) technique, poor clinical accuracy, the low confirmatory rate in the screening of suspected microdeletions and failure to detect other than the targeted microdeletion are the major drawbacks of this method [10]. So the golden standard method for detecting 22q11.2 microdeletions remains chromosomal microarray performed in invasively obtained prenatal samples, such as chorionic villi and amniotic fluid, as it was in our case.…”

Clinical Course and Outcome of Prenatally Detected 22q11.2 Deletion Syndrome—A Retrospective Analysis

“…CMA is currently used as the gold-standard method to detect microdeletion syndromes due to having a high diagnostic accuracy locating also atypical or smaller deletions, whereas FISH only detects typical sized deletions [ 27 , 28 ]. On the other hand, FISH analysis is known to be a much faster method than CMA, increasing the chances of prompt prenatal genetic confirmation within a few days.…”

Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors

“…This hypothesis is also supported by the evidence that, in the familial forms, the disease is usually inherited from the mother [ 13 , 14 ]. Apart from the most recognizable aspects, more than 180 different phenotypic features have been described [ 15 , 16 , 17 ] in 22q11.2DS patients, and the syndrome is characterized by the extreme variability of the type and severity of the clinical manifestations, which can be also observed in members of the same family [ 1 , 15 , 18 , 19 , 20 , 21 , 22 ]. The phenotypic variability consists of a different combination of clinical manifestations, which compose a syndromic picture with various degrees of severity.…”