Genetics of Chromosome 22q11.2 Deletion Syndrome

Abstract

The 22q11.2 deletion syndrome is the most frequent deletion syndrome in humans. The genomic architecture of this chromosomal region makes it prone to anomalous meiotic rearrangements causing the loss of genetic material in the parental gamete. Gene dosage‐dependent embryonic developmental processes are subsequently disrupted and lead to multiple birth malformations, the severity of which is modulated by other unknown genetic and environmental factors. The resulting clinical picture is a heterogeneous phenotype with no correlation with the genetic lesion. Currently, genetic diagnosis is mostly performed by gene dosage quantification techniques targeting region 22q11.2, but the recent development of whole‐genome scanning methods enabling a full molecular characterisation of patients under uniform criteria and a better genotype–phenotype correlation will help to understand the pathogenesis of this disorder. Key Concepts: The 22q11.2 deletion syndrome is the most common human microdeletion syndrome. It usually occurs de novo , although an estimated 10% of cases are inherited. LCR22s are homologous DNA sequences that spontaneously mediate the deletion process during meiosis. Parents should be studied both genomically and cytogenetically to rule out carrier status or occasional balanced rearrangements. Phenotypic variability is likely to be due to genetic and environmental factors during development, and it hampers a genotype–phenotype correlation. Genomic techniques will contribute to a better genotypic characterisation and understanding of the disease.