2. 22q11.2 Deletion Syndrome (22q11DS)
● Failure of 3rd and 4th pharyngeal pouches and 4th branchial arch to form, which
leads to congenital heart disease and abnormalities of the parathyroid and thymus
glands● First recognized in 1829, but
first named in 1965
● AKA DiGeorge’s Syndrome,
velocardiofacial syndrome,
cardiofacial syndrome, and
conotruncal anomaly face
syndrome
● Classification and nomenclature
has evolved since
3. Incidence and Prevalence
● 22q11.2 deletions occur in up to 1:4000 live
births, making it one of the most common
microdeletion syndromes in humans
● 500 to 750 new cases of 22q11.2DS will be
identified yearly
4. Diagnosis
● Prenatal diagnosis can be made and is indicated if a
previous child has 22q11.2DS, an affected parent has
22q11.2DS, or if there is a visible congenital heart
defect on a prenatal ultrasound
● Amniocentesis for FISH analysis at locus 22q11.2
● Postnatally, FISH analysis, MLPA testing, or
chromosomal microarray can be performed on patients
with a clinical phenotype
● < 5% of individuals with clinical findings of 22q11.2DS
have normal genetic testing
5. Phenotype
● Both sexes and all races are affected
● Symptoms can affect almost every system of the body
○ Cardiac defects
○ Palatal abnormalities
○ Distinct facial features
○ Learning disabilities
○ Immune deficiency
○ Hypocalcemia
○ Feeding and swallowing problems
○ Renal anomalies
○ Hearing loss
○ Laryngotracheoesophageal anomalies
○ CNS anomalies including tethered cord
○ Skeletal abnormalities
○ Ophthalmic abnormalities
6. Phenotypic measures
● Phenotypic variability varies widely
● There is no grading or classification system to measure the phenotypic
penetrance
7. Genotype
● 22q11.2DS is a single gene disease
● Autosomal dominant inheritance
● Subject to a high frequency of de novo
genomic rearrangement as a result of
several large paralogous low copy
repeats (LCRs)
● There are 8 LCRs on chromosome 22q11, 4 of which have been most
frequently associated with 22q11.2 deletion syndrome
● TBX1 accounts for 85% of individuals and is associated with most phenotypic
presentations
8. Genetic Counseling
● Parents of a proband
○ Parents should be evaluated using FISH or
MLPA testing
● Siblings of a proband
○ If parents have normal studies, then the risk
to siblings is low
○ If a parent also has 22q11.2DS, then the
risk to each sibling is 50%
● Offspring of a proband
○ Children have a 50% chance of inheriting
22q11.2DS
● Other family members of a proband
○ Other family members are at risk if the
parent has the deletion
9. Related Genetic Counseling Issues
● Family planning
○ Offer genetic counseling to young adults who are affected or at risk
● High-risk pregnancies
○ FISH, MLPA or microarray studies based on family history via amniocentesis between 15 to 18
weeks or CVS 10-12 weeks gestation
○ High-resolution ultrasound between 18 to 22 weeks gestation to screen for palate or cardiac
anomalies
○ Preimplantation genetic diagnosis is an option
● Low-risk pregnancies
○ FISH, MLPA or microarray recommended after prenatal findings of cleft palate and
conotruncal cardiac anomalies, such as interrupted aortic arch, tetralogy of Fallot, and VSD
○ Establishing a diagnosis even in late gestation can be useful for the early initiation of postnatal
interventions
10. References
Gao, S., Li, X. & Amendt, B.A. (2013). Understanding the role of TBX1 as a candidate gene for 22q11.2 deletion syndrome. Current Allergy and
Asthma Reports, 13(6), 613-621.
Lee, J. (2018). DiGeorge syndrome (22q11.2 deletion syndrome). The Oncofertility Consortium.
McDonald-McGinn, D.M., Emanuel, B.S. & Zackai, E.H. (1999). 22q11.2 deletion syndrome. GeneReviews.
Rauch, A., Zink, S., Zweier, C., Thiel, C.T., Koch, A., Rauch, R., Lascorz, J., Huffmeier, U., Weyand, M., Singer, H. & Hofebeck, M. (2005). Journal of
Medical Genetics, 42(11), 871-876.
Editor's Notes
First described in 1829 In the London Medical Gazette, as a constellation of symptoms accompanied by an absent thymus
In 1955, Dr. Sedlackova, a Czech phoniatrician, identified a cohort of 26 children with congenital short soft palate, hypernasal speech, facial and ear dysmorphisms, and muscle fiber abnormalities. He referred to this syndrome as velofacial hypoplasia
In 1965, Dr. Angelo DiGeorge coined the term DiGeorge anomalad, which described children with hypocalcemia, hypoparathyroidism, immune deficiency, and cardiac defects
In 1978, Shprintzen and colleagues described a group of children with a distinct nose with a squared nasal root and bulbous tip, micrognathia, cardiovascular defects, cleft palate, and developmental delays, which they called velocardiofacial syndrome.
It is now recommended that patients with confirmed 22q11.2 deletion syndrome be described according to the genetic nomenclature. Patients with clinical phenotypic diagnosis are described using syndromic nomenclature, such as DiGeorge Syndrome or Velocardiofacial Syndrome.
Two studies have shown that 22q11.2 deletions can be detected in 1/347 to 1/992 fetuses
The phenotypic presentation can vary widely, so this is likely an underestimation since many people may have the disease and not realize it
With 2.5 million children born in the united states, approximately 500 to 750 new cases of 22q11.2DS are identified yearly
Even though recurrence risk is low to have another child with 22q11.2DS, there is a possibility for a germline mosacism
The most common heart defect associated with 22q11.2DS that is diagnosed on prenatal US is a conotruncal cardiac defect.\
Conotruncal heart malformations are a group of congenital cardiac outflow tract anomalies that include such defects as tetralogy of Fallot, pulmonary atresia with ventricular septal defect, double-outlet right ventricle (DORV), double-outlet left ventricle, truncus arteriosus and transposition of the great arteries (TGA) (see these terms), among others
Postnatally, FISH analysis is most appropriate if 22q11.2DS is suspected based on clinical features. The results are available rapidly, but it is expensive. MLPA testing has a relatively low cost, and has a higher sensitvity for 22q11.2 deletions. A microarray is most appropriate if the phenotype is non-specific and is most commonly performed in the work-up of a developmental delay
Though all races can be affected, studies show that it is more commonly diagnosed in Caucasians. African-Americans may display different craniofacial abnormalities, and facial dysmorphisms are under-recognized in asians
Cardiac defects 70%, particularly conotruncal malformations including tetrology of fallot, interrupted aortic arch, VSD, and truncus arteriosis
Palatal abnormalities 69% including velopharyngeal incompetence (which is characterized by hypernasal speech caused by air escape through the nose during phonation, as a result of incomplete closure of the velum and hard palate, submucous cleft palate, bifid uvula, and cleft palate
Distinct facial features The facial features include a distinct nose with a squared nasal root and bulbous nasal tip, micrognathia
Learning disabilities 70-90%
Immune deficiency 77%
Hypocalcemia 50% which is often associated with seizures
Feeding and swallowing problems, including constipation, intestinal malrotation, imperforate anus, and Hirschsprung disease
Renal anomalies 31%
Hearing loss, both conductive and sensorineural
Laryngotracheoesophageal anomalies
CNS anomalies including tethered cord
Skeletal abnormalities, including scoliosis, clubbed feet, polydactyly, and craniosynostosis
Ophthalmic abnormalities, including strabismus and tortuous retinal vessels
Phenotype can vary widely even among those in the same family
It has autosomal dominant inheritance, but 93% of probands have a de novo mutation and 7% inherited the 22q11.2 deletion from a parent
LCRs mediate atypical interchromosomal exchanges during meiosis, with 22q11 deletions being among the most frequent rearrangements
Several other genetic disorders are also medicated by LCRs, including Prader-Willi, Angelman, Williams, Neurofibromatosis 1, and Sotos syndrome.
These 4 LCRs are the largest and share 98% of their sequence identity, which contributes to the higher rate of aberrante xchanges
Parents: even mildly affected adults, and normal adults with somatic mosaicsm, have been identified
Siblings: even if parents appear to not have the disease, the risk to the sibling of the proband is low but greater than the general population, since parents can have germline mosaicism or low-level somatic mosaicism
