22q11.2 deletion syndrome epidemiology and demographics
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ayushi Jain, M.B.B.S[3]
Overview
Epidemiology and Demographics
The estimated prevalence has been cited in several studies as being 1:3000-1:6000 births. These estimates are based on extrapolations of limited populations that have been screened using fluorescent in situ hybridization (FISH) technology. Males and females are equally affected, and there is no population "founder" effect. The deletion arises de novo frequently in all populations, and there is no reason to believe that the syndrome is more frequent in any particular ethnic background. The existing data do not yet take into account the rising prevalence due to increasing numbers of affected adults having their own affected children. Since this is a haplosufficiency disorder, one-half of the children of affected adults will have the deletion. Therefore, the prevalence is anticipated to rise over time. Currently, the figures are 6%-10% of new cases are familial. Since survival with cardiac anomalies was low until the mid-1980s, the familial cases are expected to rise. Moreover, within the Children's Hospital of Philadelphia (CHOP) cohort, the familial rate for patients with an atypical deletion such as the "B-D" deletion is much higher (5/11 or 45%), suggesting that those patients with a seemingly milder phenotype are more likely to reproduce.
Recent studies using SNP arrays have suggested that there are atypical deletions not detected by FISH-based strategies, and the true prevalence may be higher than suspected when these variants are included (see below). Commercial laboratories have reported classical deletions in approximately 1:100-1:200 samples sent for SNP array testing, and atypical deletions with approximately half of that frequency (Lisa Shaffer, Signature Genomics, personal communication). These laboratory sets represent patient cohorts with underlying medical problems but give valuable information on the relative frequencies of the typical and atypical deletions. Many of the atypical deletions would not have been identified with FISH technology, leading to the belief that we currently underascertain patients with the deletion.
While the frequency in the general population is slightly less frequent than trisomy 21, it is still sufficiently common that chromosome 22q11.2 deletion can occur in combination with other diagnoses. We have seen patients with Marfan syndrome and chromosome 22q11.2 deletion syndrome, Ehlers-Danlos and chromosome 22q11.2 deletion syndrome, and trisomy 21 and chromosome 22q11.2 deletion syndrome. There have also been distant family members with the deletion where it arose on completely distinct haplotypes and therefore represent distinct de novo events.
An important clinical aspect in the consideration of the demographic characteristics of the deletion is the frequency in unselected populations with compatible phenotypic features. The variability of the phenotypic features has made it difficult to define the exact clinical scenario where testing is warranted. Various algorithms have been developed to identify patient groups for whom testing for the deletion is clearly clinically warranted. These algorithms have thus far been disappointing at identifying patients outside of the most classic phenotype. Nevertheless, multiple studies have identified the frequency of the deletion in specific patient groups, and these data provide valuable context when considering the diagnostic approach (