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Cited by 137Genomic variations and chromosomal abnormalitiesGenome Rearrangement AlgorithmsGenetics and Neurodevelopmental Disorders

Molecular genetics of 22q11.2 deletion syndrome

Open access
Morrow, Bernice E., McDonald‐McGinn, Donna M., Emanuel, Beverly S., Vermeesch, Joris R., Scambler, Peter J.·2018·American Journal of Medical Genetics Part A
DOI 10.1002/ajmg.a.40504PMC PMC6214629
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Abstract

The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by meiotic chromosome rearrangements. One of the goals of this review is to summarize the current state of basic research studies of 22q11.2DS. It highlights efforts to understand the mechanisms responsible for the 22q11.2 deletion that occurs in meiosis. This mechanism involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2 region and the deletion is mediated by nonallelic homologous recombination events. This review also highlights selected genes mapping to the 22q11.2 region that may contribute to the typical clinical findings associated with the disorder and explain that mutations in genes on the remaining allele can uncover rare recessive conditions. Another important aspect of 22q11.2DS is the existence of phenotypic heterogeneity. While some patients are mildly affected, others have severe medical, cognitive, and/or psychiatric challenges. Variability may be due in part to the presence of genetic modifiers. This review discusses current genome‐wide efforts to identify such modifiers that could shed light on molecular pathways required for normal human development, cognition or behavior.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes the molecular genetics of 22q11.2 deletion syndrome (22q11.2DS), emphasizing meiotic non-allelic homologous recombination between LCR22 low-copy repeats, candidate genes such as TBX1 and CRKL, unmasking of recessive mutations, and phenotypic variability. It also discusses genome-wide efforts to identify genetic modifiers of congenital heart disease and schizophrenia.

Key findings

  • 22q11.2DS occurs in ~1/4000 live births and 1/1000 fetuses; most individuals have a de novo 1.5–3 Mb deletion, approximately 5% are inherited, and over 90% have the LCR22A-D deletion type, with LCR22A-B (1.5 Mb) second most common and LCR22A-C (2.0 Mb) least frequent.
  • TBX1 in the LCR22A-B region is a major contributor to medical features; heterozygous TBX1 mutations mimic 22q11.2DS defects, and mouse models show dosage sensitivity. CRKL in LCR22C-D acts in the same pathway and is required for thymus, parathyroid, aortic arch, heart, and genitourinary development.
  • Recessive mutations on the remaining allele can unmask additional conditions; genes listed include PRODH, SLC25A1, CDC45, GP1BB, and TANGO2 in LCR22A-B, SCARF2 in LCR22B-C, and SNAP29 in LCR22C-D. Somatic loss of heterozygosity plus LZTR1 mutation predisposes to multiple schwannomas.
  • Phenotypic variability occurs despite typically similar deletion size: 60–70% have congenital heart disease and 25% develop schizophrenia; in a schizophrenia analysis of 21,094 cases and 20,227 controls, the 22q11.2 deletion was the most significantly associated copy number variation. Modifiers include CNVs such as a SLC2A3 duplication, chromatin-modifier genes, and rare CNVs.

Methods

  • Narrative review of basic, clinical, and molecular genetic studies; no primary cohort or new experimental data are presented.
  • Synthesizes literature on meiotic NAHR and LCR22 structure, clinical testing (FISH, MLPA, microarray), candidate genes, mouse models, recessive unmasking, and genetic modifiers.
  • Cites specific analyses, including Affymetrix 6.0 arrays in almost 1,000 subjects with 22q11.2DS, whole exome sequencing in 184 individuals, whole genome sequencing in >1,500 subjects underway, and a schizophrenia GWAS of 21,094 cases and 20,227 controls.

Limitations

  • The paper states that LCR22 structure is complex and difficult to map, that traditional sequencing has been only partially successful, and that identifying chromosome breakpoints in deleted patients remains challenging.
  • The paper states that more patients with atypical LCR22B-D or C-D deletions need to be analyzed to understand the range and severity of anomalies and whether schizophrenia is an important feature; roles of COMT, PRODH, and PIK4CA remain controversial, and more studies are needed in humans.
  • Evident from the text: as a narrative review, it does not describe a systematic literature search or quality appraisal, and many modifier findings are described as ongoing, controversial, or not yet definitive.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/ajmg.a.40504

Cites

146 of 146 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 104 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    TBX1 has a major role in the medical aspects of 22q11.2DS.

    “This gene has received much attention for a major role in medical aspects of the disorder.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Castellanos, Xie, Zheng, Cvekl, & Morrow, 2014

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    • cites Gong et al., 2001

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    • cites Griffin et al., 2010

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  • Premisecitation

    Heterozygous mutations in TBX1 have been identified in patients with defects similar to those in 22q11.2DS.

    “Heterozygous mutations within TBX1 have been identified in patients with similar defects as occurs in those with 22q11.2DS”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Castellanos, Xie, Zheng, Cvekl, & Morrow, 2014

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    • cites Gong et al., 2001

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    • cites Griffin et al., 2010

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  • Premisecitation

    Each LCR22 is a complex mosaic of modules that has been difficult to map precisely in humans.

    “Each LCR22 is a complex mosaic of modules that has been challenging to precisely map in humans.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites X. Guo et al., 2016

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    • cites X. Guo, Freyer, Morrow, & Zheng, 2011

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    • Rests on an assumption: The 22q11.2 region contains eight LCR22 repeats, designated LCR22A through LCR22H.
  • Premisecitation

    Patients with LCR22B-D or C-D deletions have some features related to typical deletions but with reduced penetrance.

    “These patients have some related features to those with the typical deletions, but they occur with reduced penetrance”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Racedo et al., 2015

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    • cites Rump et al., 2014

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  • Premisecitation

    22q11.2 deletion syndrome is a congenital malformation and neuropsychiatric disorder caused by meiotic chromosome rearrangements.

    “The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by meiotic chromosome rearrangements.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Edelmann, Pandita, & Morrow, 1999

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    • cites Edelmann, Pandita, Spiteri, et al., 1999

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    • cites Shaikh et al., 2000

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  • May combine two claims. 19
  • Classified as probably not a substantial claim. 4
  • The quote only partly states this claim. 1

  • May combine two claims.

    Interpretationreasoning

    FISH probes N25 or TUPLE map to LCR22A-B, so they detect typical deletions but miss atypical nested deletions outside A-B.

    “The two FISH probes map to the LCR22A-B region, thus the probes will identify typical deletions, but would miss atypical nested deletions that occur outside the A-B region.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 22q11.2 region contains eight LCR22 repeats, designated LCR22A through LCR22H.
    • Rests on an assumption: Four LCR22 repeats (A–D) lie within the 3 Mb region associated with 22q11.2DS.

  • May combine two claims.

    Interpretationcitation

    Different tissues and organs have different degrees of sensitivity to Tbx1 dosage, suggesting altered regulation of its expression could explain phenotypic variability in patients.

    “different tissues and organs have different degrees of sensitivity to Tbx1 dosage and suggests that altered regulation of its expression could explain phenotypic variability in patients”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Z. Zhang & Baldini, 2008

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  • May combine two claims.

    Premisecitation

    MLPA has probes spaced throughout 22q11.2 and can identify typical and atypical deletions.

    “Multiplex Ligation-dependent Probe Amplification (MLPA) has probes that are spaced throughout the 22q11.2 region and can be used to identify typical and atypical deletions”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fernandez et al., 2005

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    • cites Vorstman et al., 2006

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  • May combine two claims.

    Interpretationreasoning

    The LCR22A-B deleted region does not overlap with LCR22B-D or C-D regions, implying that haploinsufficiency of different genes can produce similar phenotypes.

    “What is truly fascinating is that the LCR22A-B deleted region does not overlap with the LCR22B-D or C-D region, ascribing haploinsufficiency of different genes to some similar phenotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The 1.5 Mb LCR22A-B deletion is the second most common deletion type, while the 2.0 Mb LCR22A-C deletion is least frequent.

    “The 1.5 Mb deletion between LCR22A-B is the second most common deletion type, while the 2.0 Mb LCRA-C deletion is least frequent”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Carlson et al., 1997

      Not checked in the free run.

    • Rests on an assumption: The 22q11.2 region contains eight LCR22 repeats, designated LCR22A through LCR22H.
    • Rests on an assumption: Four LCR22 repeats (A–D) lie within the 3 Mb region associated with 22q11.2DS.

  • May combine two claims.

    Premisecitation

    Tbx1 is expressed and functions in all three germ layers of the pharyngeal apparatus: endoderm, mesoderm, and ectoderm.

    “Tbx1 is expressed and functions in all three germ layers of the pharyngeal apparatus, namely the endoderm”
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    • cites Arnold et al., 2006

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    • cites Jackson, Kasah, Mansour, Morrow, & Basson, 2014

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    • cites Z. Zhang et al., 2005

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  • May combine two claims.

    Interpretationreasoning

    LCR22A and LCR22D are the largest and most homologous LCR22s, making them good targets for NAHR.

    “LCR22A and LCR22D are the largest in size and have the most homology to each other, making them good targets for NAHR events.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 22q11.2 region contains eight LCR22 repeats, designated LCR22A through LCR22H.
    • Rests on an assumption: Four LCR22 repeats (A–D) lie within the 3 Mb region associated with 22q11.2DS.

  • May combine two claims.

    Premisecitation

    In mouse models, inactivating one Tbx1 allele causes mild cardiovascular defects, while inactivating both alleles causes cleft palate, thymic and parathyroid gland aplasia, and cardiovascular defects.

    “Inactivation of one allele resulted in mild cardiovascular defects, but inactivation of both alleles resulted in cleft palate, thymic and parathyroid gland aplasia as well as cardiovascular defects”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Jerome & Papaioannou, 2001

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    • cites Lindsay et al., 2001

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    • cites Merscher et al., 2001

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  • May combine two claims.

    Premisecitation

    HIC2 maps near the distal end of LCR22D and is not usually deleted, but some atypical longer LCR22D deletions extend beyond HIC2.

    “HIC2 maps to a small unique genomic region near the distal end of LCR22D and it is not usually deleted in patients. However, some individuals have atypical longer deletions in LCR22D that extend beyond HIC2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dykes et al., 2014

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DGCR8 encodes a subunit of a microprocessor complex that mediates miRNA biogenesis.

    “This gene encodes a subunit of a microprocessor complex that mediates the biogenesis of miRNAs”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gregory et al., 2004

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    Premisecitation

    Neural crest cells delaminate and migrate from the neural tube and make a major contribution to morphogenesis of structures affected in 22q11.2DS.

    “Neural crest cells comprise a population of cells that delaminates and migrates from the neural tube. These cells make a major contribution to morphogenesis of the structures affected in 22q11.2DS”
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    • cites Calmont et al., 2009

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PIK4CA encodes phosphatidylinositol 4-kinase alpha and has been considered a schizophrenia candidate, but this remains controversial.

    “This gene encodes Phosphatidylinositol 4-kinase alpha and has been considered a candidate for schizophrenia, although this possibility remains controversial”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ikeda et al., 2010

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    • cites Vorstman et al., 2009

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    Premisecitation

    The role of reduced COMT enzyme activity in causing cognitive and/or behavioural deficits is controversial; some studies support it and others do not.

    “While some studies support a role of reduced enzyme activity of COMT to cause cognitive and/or behavioural deficits, others do not, and the importance of this functional variation in COMT remains controversial”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Armando, Papaleo, & Vicari, 2012

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    • cites Franconi et al., 2016

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  • May combine two claims.

    Premisecitation

    Direct downstream transcriptional target genes of TBX1 have been discovered and a link between TBX1 and chromatin modification has been identified.

    “Recently, direct downstream transcriptional target genes of TBX1 protein were discovered and a link to chromatin modification in connection with TBX1 was identified”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Baldini, Fulcoli, & Illingworth, 2017

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    • cites Fulcoli et al., 2016

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Recessive mutations in essential genes would likely cause early embryonic lethality and thus not be identifiable in the human population.

    “recessive mutations in essential genes would likely cause early embryonic lethality, in which we would not be able to identify in the human population”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    60-70% of 22q11.2DS patients have congenital heart disease, including various aortic arch and/or cardiac outflow tract anomalies.

    “60–70% have congenital heart disease, which includes many different aortic arch and/or cardiac outflow tract anomalies”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Goldmuntz et al., 1993

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    • cites McDonald-McGinn et al., 2015

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    • cites Swillen & McDonald-McGinn, 2015

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  • May combine two claims.

    Premisecitation

    SCARF2 maps to LCR22B-C, and SNAP29 maps to LCR22C-D.

    “SCARF2 [Scavenger receptor class F member 2; (Bedeschi et al., 2010)] maps to the LCR22B-C region, while SNAP29 [Synaptosome associated protein 29; (T. Hsu et al., 2017; McDonald-McGinn et al., 2013; Sprecher et al., 2005)] maps to the LCR22C-D region.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bedeschi et al., 2010

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    • cites T. Hsu et al., 2017

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    • cites McDonald-McGinn et al., 2013

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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Whole exome sequencing on 184 individuals with 22q11DS, roughly half with severe cardiac anomalies and half without, identified genes important for chromatin modification as altering risk and additional genes with rare possible damaging variants for cardiac development.

    “Whole exome sequencing on 184 individuals with 22q11DS, in which roughly half had severe cardiac anomalies and half had no defect, identified genes important for chromatin modification as altering risk”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites T. Guo et al., 2015

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    • cites Lin, Zhang, Cai, Morrow, & Zhang, 2017

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  • May combine two claims.

    Premisecitation

    Analysis of rare CNVs altering risk to cardiovascular anomalies found no specific increased burden of CNVs, but CNVs harboring genes important for cardiovascular development may play a role in this sensitized population.

    “Analysis of rare CNVs that alter risk to cardiovascular anomalies has been more challenging, with no specific increased burden of CNVs, but it is possible, when taken together that CNVs harboring genes important for cardiovascular development play a role in this sensitized population”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mlynarski et al., 2016

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  • May combine two claims.

    Premisecitation

    Five genes-PRODH, SLC25A1, CDC45, GP1BB, and TANGO2-map to LCR22A-B and harbor autosomal recessive mutations.

    “Five genes, PRODH”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Afenjar et al., 2007

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    • cites Edvardson et al., 2013

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    • cites Fenwick et al., 2016

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  • May combine two claims.

    Premisecitation

    Rare CNVs contribute to schizophrenia and 22q11.2DS.

    “Recently, rare CNVs were shown to contribute to schizophrenia and 22q11.2DS”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bassett et al., 2017

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21 of 21

  • The paper relies on this without support.

    The 22q11.2 region contains eight LCR22 repeats, designated LCR22A through LCR22H.

    “There are eight LCR22s that span the 22q11.2 region termed LCR22A through -H.”

  • The paper relies on this without support.

    Four LCR22 repeats (A–D) lie within the 3 Mb region associated with 22q11.2DS.

    “There are four LCR22s that map to the 3 Mb region associated with the disorder and they are termed LCR22A, -B, -C and –D.”

  • The paper relies on this without support.

    In more than 90% of 22q11.2DS patients, the interval between LCR22A and LCR22D is hemizygously deleted.

    “In over 90% of patients, the region between LCR22A-D is hemizygously deleted.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 57 genes in the 22q11.2 locus were expressed in hCS, overlapping with 67 genes from that region expressed in human fetal brain.

    “We found that 57 genes were expressed in the hCS, which overlapped with the 67 genes from that region shown to be expressed in human fetal brain (Extended Data Fig. 2f)28.”

    From Neuronal defects in a human cellular model of 22q11.2 deletion syndrome (2020) · cites this paper as [28]

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Related

Authors
Morrow, B. E., McDonald‐McGinn, D. M., Emanuel, B. S., Vermeesch, J. R., & Scambler, P. J.
Affiliations
  • Albert Einstein College of Medicine (US)
  • Children's Hospital of Philadelphia (US)
  • KU Leuven (BE)
  • University College London (GB)
Corresponding author
Morrow, Bernice E.
ORCID
Venue
American Journal of Medical Genetics Part A
Publisher
Wiley
Published
2018-10
Volume
176
Issue
10
Pages
2070-2081
ISSN
  • 1552-4825 (ISSN-L)
  • 1552-4833
DOI
10.1002/ajmg.a.40504
PMC
PMC6214629
OpenAlex
W2899016780
Semantic Scholar
940bde48320ad7836f54e8e0ec6d8038c75d650b
Cited by
137
References
146
Citations by year
2026: 8 · 2025: 12 · 2024: 21 · 2023: 24 · 2022: 31 · 2021: 15 · 2020: 17 · 2019: 9
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 30 d)
Locations
  • American Journal of Medical Genetics Part A (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lirias (KU Leuven) (submittedVersion)
Funders
  • British Heart Foundation (PG/09/065/27893)
  • Fondation Jérôme Lejeune (#1665)
  • Fondation Leducq
  • National Heart, Lung, and Blood Institute (HL132577)
  • National Institute of Child Health and Human Development (HD070454)
  • National Institute of Mental Health (MH087636MH101720)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
22q11.2 deletion syndrome, segmental duplication, non-allelic homologous recombination, phenotypic heterogeneity, genetic modifiers, recessive mutations, congenital malformations, neuropsychiatric disorders, gene mapping
MeSH terms
Abnormalities, Multiple, Chromosome Deletion, Chromosomes, Human, Pair 22, DiGeorge Syndrome, Genes, Recessive, Genetic Testing, Humans, Meiosis, Mutation

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