Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan 6;14(1):160.
doi: 10.3390/genes14010160.

Prenatal Screening and Diagnostic Considerations for 22q11.2 Microdeletions

Natalie Blagowidow  1 , Beata Nowakowska  2 , Erica Schindewolf  3 , Francesca Romana Grati  4 , Carolina Putotto  5 , Jeroen Breckpot  6 , Ann Swillen  6 , Terrence Blaine Crowley  7 , Joanne C Y Loo  8 , Lauren A Lairson  7 , Sólveig Óskarsdóttir  9   10 , Erik Boot  8   11   12 , Sixto Garcia-Minaur  13 , Maria Cristina Digilio  14 , Bruno Marino  5 , Beverly Coleman  3   15 , Julie S Moldenhauer  3   16 , Anne S Bassett  8   17   18 , Donna M McDonald-McGinn  7   19   20
Affiliations
Review

Prenatal Screening and Diagnostic Considerations for 22q11.2 Microdeletions

Natalie Blagowidow et al. Genes (Basel). .

Abstract

Diagnosis of a chromosome 22q11.2 microdeletion and its associated deletion syndrome (22q11.2DS) is optimally made early. We reviewed the available literature to provide contemporary guidance and recommendations related to the prenatal period. Indications for prenatal diagnostic testing include a parent or child with the 22q11.2 microdeletion or suggestive prenatal screening results. Definitive diagnosis by genetic testing of chorionic villi or amniocytes using a chromosomal microarray will detect clinically relevant microdeletions. Screening options include noninvasive prenatal screening (NIPS) and imaging. The potential benefits and limitations of each screening method should be clearly conveyed. NIPS, a genetic option available from 10 weeks gestational age, has a 70-83% detection rate and a 40-50% PPV for most associated 22q11.2 microdeletions. Prenatal imaging, usually by ultrasound, can detect several physical features associated with 22q11.2DS. Findings vary, related to detection methods, gestational age, and relative specificity. Conotruncal cardiac anomalies are more strongly associated than skeletal, urinary tract, or other congenital anomalies such as thymic hypoplasia or cavum septi pellucidi dilatation. Among others, intrauterine growth restriction and polyhydramnios are additional associated, prenatally detectable signs. Preconception genetic counselling should be offered to males and females with 22q11.2DS, as there is a 50% risk of transmission in each pregnancy. A previous history of a de novo 22q11.2 microdeletion conveys a low risk of recurrence. Prenatal genetic counselling includes an offer of screening or diagnostic testing and discussion of results. The goal is to facilitate optimal perinatal care.

Keywords: 22q11.2 deletion syndrome; fetal cardiac anomaly; noninvasive prenatal screening; preimplantation genetic testing; prenatal ultrasound.

PubMed Disclaimer

Conflict of interest statement

F.R.G. is a full-time employee as chief genomics officer at Menarini Biomarkers Singapore.

Figures

Figure 1
Figure 1
22q11.2 non-allelic homologous recombination [1]. Diagram of two different types of meiotic non-allelic homologous recombination events that can occur between low copy repeats on chromosome 22 (LCR22s), at spermatogenesis or oogenesis. Rearrangements between LCR22A and LCR22D are indicated (A and D) on each allele (blue versus yellow). Interchromosomal events (left) occur between paralogous LCR22s (A and D) in two different alleles owing to >99% sequence identity of direct repeats (“X” shows the crossover of the two chromosomes). The hybrid LCR22 is shown as half yellow and half blue. This process results in a duplication or deletion of the intervening region and genes in resulting gametes. Intrachromosomal recombination events (right) result from crossing over (indicated by red “X”) within one allele, resulting in a deletion (left) or a ring chromosome (right); the ring chromosome is not viable [1].
Figure 2
Figure 2
Chromosome 22 ideogram and low copy repeats that span this region. Chromosome 22 ideogram (left). Cytogenetic representation of chromosome 22 showing the short (p) and long (q) arms along with the centromere, which functions to separate both arms. Chromosome 22 is an acrocentric chromosome, as indicated by the two horizontal lines in the p arm. The 22q11.2 deletion occurs on the long arm of one of the two chromosomes, depicted by dashed lines in the 22q11.2 band. The position of the two low copy repeats (LCRs) on 22q11.2 (LCR22A and LCR22D), which flank the typical 2.5 to 3 Mb deletion (length varies when including/not including the LCRs), are indicated. Low copy repeats and genes within the 22q11.2 deletion (right). Schematic representation of the 2.5 to 3 Mb 22q11.2 region that is commonly deleted in 22q11.2 deletion syndrome, including the four low copy repeats (LCR22s) that span this region (LCR22A, LCR22B, LCR22C, and LCR22D). Common commercial probes for fluorescence in situ hybridization (FISH) are indicated (N25 and TUPLE). Selected protein-coding (and non-coding*) genes are indicated with respect to their relative position along chromosome 22 (Chr22). T-box 1 (TBX1; green box) is highlighted as the most widely studied gene within the 22q11.2 region. Mutations in this gene have resulted in conotruncal cardiac anomalies in animal models and humans. The CRK Like Proto-Oncogene, Adaptor Protein, also known as V-Crk Avian Sarcoma Virus CT10 Oncogene Homolog-Like, (CRKL; located between LCR22C and LCR22D) gene has been associated with renal/urogenital and congenital cardiac anomalies [1].
Figure 3
Figure 3
Flow chart of search strategy methods and results.
Figure 4
Figure 4
22q11.2DS Structural Findings. Range of proportion of fetuses with prenatal structural findings in nine categories, later found to have a diagnosis of 22q11.2DS. Based on data from studies with 40 or more patients [6,11,38,39,41]. Legend: GU, genito-urinary tract; Poly: polyhydramnios; CNS: central nervous system, GI: gastrointestinal.
Figure 5
Figure 5
Second- and third-trimester ultrasound findings in 22q11.2DS. (A) Tetralogy of Fallot, overriding aorta (arrow), (B) normal thymus, (C) hypoplastic thymus, (D) normal cavum septi pellucidi (CSP), (E) enlarged CSP, (F) talipes equinovarus (arrow), (G) profile with bulbous nose, (H) face with bulbous nose, (I) small ear with thickened overfolded helix. (B through E—areas of interest are indicated by calipers).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. McDonald-McGinn D.M., Sullivan K.E., Marino B., Philip N., Swillen A., Vorstman J.A.S., Zackai E.H., Emanuel B.S., Vermeesch J.R., Morrow B.E., et al. 22q11.2 Deletion Syndrome. Nat. Rev. Dis. Prim. 2015;1:15071. doi: 10.1038/nrdp.2015.71. - DOI - PMC - PubMed
    1. Blagojevic C., Heung T., Theriault M., Tomita-Mitchell A., Chakraborty P., Kernohan K., Bulman D.E., Bassett A.S. Estimate of the Contemporary Live-Birth Prevalence of Recurrent 22q11.2 Deletions: A Cross-Sectional Analysis from Population-Based Newborn Screening. CMAJ Open. 2021;9:E802–E809. doi: 10.9778/cmajo.20200294. - DOI - PMC - PubMed
    1. Grati F.R., Molina Gomes D., Ferreira J.C.P.B., Dupont C., Alesi V., Gouas L., Horelli-Kuitunen N., Choy K.W., García-Herrero S., de la Vega A.G., et al. Prevalence of Recurrent Pathogenic Microdeletions and Microduplications in over 9500 Pregnancies. Prenat. Diagn. 2015;35:801–809. doi: 10.1002/pd.4613. - DOI - PubMed
    1. Maisenbacher M.K., Merrion K., Pettersen B., Young M., Paik K., Iyengar S., Kareht S., Sigurjonsson S., Demko Z.P., Martin K.A. Incidence of the 22q11.2 Deletion in a Large Cohort of Miscarriage Samples. Mol. Cytogenet. 2017;10:6. doi: 10.1186/s13039-017-0308-6. - DOI - PMC - PubMed
    1. Kowalczyk K., Bartnik-Głaska M., Smyk M., Plaskota I., Bernaciak J., Kędzior M., Wiśniowiecka-Kowalnik B., Jakubów-Durska K., Braun-Walicka N., Barczyk A., et al. Prenatal Diagnosis by Array Comparative Genomic Hybridization in Fetuses with Cardiac Abnormalities. Genes. 2021;12:2021. doi: 10.3390/genes12122021. - DOI - PMC - PubMed