Chapter 1 - 22q11.2 deletion syndrome: Setting the stage

Abstract

The chromosome 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion thought to result from de novo nonallelic homologous meiotic recombination events in the majority of affected individuals, resulting in loss of ~ 50 genes in this ~ 2.5Mb hemizygous deletion, occurring in approximately 1 in 1000 fetuses and 1 in 2000–6000 live births, and leading to significant morbidity and some mortality. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the mid-1960s in children with DiGeorge syndrome (DGS), who presented with the clinical triad of immunodeficiency, hypoparathyroidism, and congenital heart disease. 22q11.2DS is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions such as palatal, gastrointestinal, renal, and skeletal anomalies, autoimmune disease, variable cognitive delays, behavioral differences, and psychiatric illness—all far extending the original description of DGS. Management requires a multidisciplinary approach involving pediatrics, general medicine, surgery, psychiatry, psychology, radiology, pathology, interventional therapies (physical, occupational, speech, language, educational, and behavioral), and genetic counseling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentations, often delays diagnosis. Early identification, preferably prenatally or neonatally, could improve outcomes, thus underscoring the importance of enhanced ascertainment, perhaps by way of newborn screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies and medical conditions including psychiatric and developmental differences, which could well provide the chance to better understand these distinct conditions while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and individuals with these associated features in the general population.