PRIMEVIEW

22q11.2 DELETION SYNDROME

For the Primer, visit doi:10.1038/nrdp.2015.71

22q11.2 deletion syndrome MANAGEMENT

MECHANISMS
(22q11.2DS) is a condition resulting
from the loss of a small fragment of
22q11.2DS has a highly variable clinical
chromosome 22, variably affecting
presentation, ranging from severe life-
multiple organ systems. Clinical features
De novo 22q11.2 deletions threatening conditions to the presence of
include congenital anomalies and later-
are the result of aberrant only a few, sometimes minor, symptoms.
onset conditions, such as cardiac and
interchromosomal exchange The presentation also varies with age. Some
palatal abnormalities; autoimmune
owing to the presence of combinations of congenital heart defects, chronic
diseases; endocrine, immune, renal and low copy repeats (LCRs)
The deletion infection, hypocalcaemia, palatal anomalies, and
gastrointestinal problems; speech and that are >95% identical and
causes developmental and language delays are frequent
language delays; and variable cognitive flank the deletion
haploinsufficiency in infancy and early childhood. In adolescence
deficits and neuropsychiatric illnesses.
of ~50 genes and and adulthood, scoliosis and learning difficulties,
7 microRNAs as well as behavioural abnormalities, in many
KL instances indicative of (emerging) psychiatric
EPIDEMIOLOGY CR illness, predominate. As a consequence,
management requires an individualized,
The 22q11.2 deletion is the most frequent TBX1 OD
H
multidisciplinary approach that takes the specific
chromosomal microdeletion with an estimated PR symptoms of each patient into account.
prevalence of 1 per 1,000 fetuses. Prevalence is 13.0
higher in fetuses with abnormal ultrasonographic GP1 DGCR8
p arm BB COMT
findings (1 per 100) or in neonates with DIAGNOSIS
developmental disabilities (1 per ~170). 22q11.2 11.1
Centromere ZDHHC8
deletion is a common cause of congenital 11.1 LCR22A 2 9
heart disease, syndromic palatal anomalies and RANBP1 SCA AP Lack of recognition of the condition, heterogeneous
11.2
22q11.2 deletion
RF2 SN
developmental delay. Most patients (>90%) have a 12.1
clinical presentation and often subtle characteristic
de novo deletion — that is, neither of their parents 12.3 LCR22D facial features frequently delay diagnosis.
have the deletion. However, individuals with q arm Fluorescence in situ hybridization using probes that
13.1
22q11.2DS have a 50% chance of transmitting the Many physical attributes associated with map to the LCR22A–LCR22B region is often used to
13.2
deletion to their offspring. Thus, the proportion of 13.31 22q11.2DS can be ascribed to problems with detect the deletion. Nested deletions can only be
13.32 morphogenesis and subsequent abnormal function
inherited disease is expected to increase owing to identified using whole-region methodologies, such
increased survival and higher reproduction rates of embryonic pharyngeal arch system derivatives, as microarray comparative genome hybridization,
in affected individuals. Approximately 85% of the deletions involve the including the craniofacial region, the thymus, multiplex ligation-dependent probe amplification
whole 3-Mb region between LCR22A and LCR22D; the parathyroid glands, the aortic arch and the
or digital PCR assays.
the remainder are nested, smaller deletions cardiac outflow tract
Cytogenetically visible deletions of 22q11.2
were initially identified in a subset of patients
with the classic triad of DiGeorge syndrome OUTLOOK
(immunodeficiency, hypoparathyroidism and
congenital heart disease) in the early 1980s. Non-deleted
Later, submicroscopic deletions at 22q11.2 were The high clinical variability region of the non-deleted deleted. Owing to the complexity
22q11.2
causally identified in the majority of patients remains largely unexplained chromosome, modifier genes of the LCRs in this region, the region
Control
probe
with DiGeorge, velocardiofacial and conotruncal and might be attributed to outside of the deleted region and exact breakpoints remain largely
anomaly face syndromes, among others. Now, the several mechanisms, including epigenetic phenomena. Another unidentified; even the latest
condition is referred to by the common factor dosage-sensitive genes, allelic outstanding question is why the genome assembly still contains 22q11.2
and cytogenetic aetiology: 22q11.2DS. variation of genes in the 22q11.2 22q11.2 region is so frequently gaps in this area. deletion

Designed by Laura Marshall Article number: 15072; doi:10.1038/nrdp.2015.72; published online 19 November 2015
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