Craniofacial Phenotypes and Genetics of DiGeorge Syndrome: Comparison
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TBX1, located on chromosome 22q11.21, encodes a T-box transcription factor and is a candidate gene for DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). Studies of Tbx1-mutant mice have provided insights into the underlying pathogenesis of DGS/VCFS and the knowledge to diagnose patients with DGS/VCFS. Genes, miRNAs, and epigenetics could change Tbx1 expression. Polymorphisms, variations, and mutations in TBX1 may induce the penetrance and severity of DGS/VCFS-like craniofacial phenotypes. The molecular basis of the variant sequence of TBX1 will further define how TBX1 contributes to the craniofacial and other phenotypes of DGS/VCFS. Since interactions with TBX1 and other molecules in transcriptional complexes or chromatin remodeling are crucial for TBX1 function, identifying and understanding these genetic and epigenetic modifiers individually for each patient may direct therapeutics to minimize the severity.

  • 22q11.2 deletion syndrome
  • DiGeorge syndrome
  • velocardiofacial syndrome
  • cleft palate
  • skull base

1. Introduction

The 22q11.2 deletion syndrome is one of the most common chromosomal microdeletions, affecting approximately 1 in 4000 live births in humans [1]. A 1.5 to 2.5 Mb hemizygous deletion of chromosome 22q11.2 causes DiGeorge syndrome (DGS; OMIM #188400) and velocardiofacial syndrome (VCFS or Shprintzen VCF syndrome; OMIM #192430) [2]. DGS/VCFS appears to be a genomic disorder distinct from 22q11.2 distal deletion syndrome (OMIM #611867). The clinical phenotype of DGS/VCFS is a complex and variable congenital disability, including cardiovascular defects, thymic hypoplasia, parathyroid hypoplasia, and craniofacial malformations [3]. Craniofacial malformations occur in approximately 60% of patients with DGS/VCFS [4].
TBX1, located on chromosome 22q11.21, encodes a T-box transcription factor and is considered a candidate gene for DGS/VCFS since mutations in TBX1 have been found in patients with DGS/VCFS [5]. Heterozygous Tbx1-mutant (Tbx1+/−) mice exhibit DGS/VCFS-related cardiovascular, parathyroid, and thymic phenotypes, suggesting that TBX1 dosage is critical for cardiovascular, parathyroid and thymic development [6][7][8][9]. Tbx1-null mice exhibit the most clinical features of DGS/VCFS, including craniofacial phenotypes, while Tbx1+/− mice exhibit no significant craniofacial phenotypes [6][7][8][9][10].
There have been some excellent reviews on genetics and cardiovascular anomalies of DGS/VCFS [3][11][12][13]. However, information on the craniofacial anomalies of DGS/VCFS is limited. This research focuses on these phenotypes and summarizes the current understanding of the genetic factors that impact DGS/VCFS-related phenotypes. The researchers also review DGS/VCFS mouse models that have been designed to better understand the pathogenic processes of DGS/VCFS.

2. Craniofacial Phenotypes of Patients with DGS/VCFS

Patients with DGS/VCFS manifest craniofacial anomalies involving the cranium, cranial base, jaws, pharyngeal muscles, ear-nose-throat, palate, teeth, and cervical spine (Table 1 and Table 2). Frequently observed craniofacial phenotypes include velopharyngeal insufficiency (27–92%), enamel hypomineralization (39–41%), hearing loss (33–39%), platybasia (50–91%), and cervical spine anomalies (75%) (Table 1). Delayed development of the hyoid bone has also been reported [14][15].
Table 1. Craniofacial anomalies in patients with DGS/VCFS.
Phenotypes Features Frequency
Palatal anomalies Overt cleft palate 7–11%
  Submucous cleft palate 5–23%
  Bifid uvula 5–10%
  Velopharyngeal insufficiency 27–92%
Dental anomalies Tooth agenesis 15%
  Hypoplasia of primary teeth 32%
  Hypoplasia of permanent teeth 10%
  Enamel hypomineralization of primary teeth 39%
  Enamel hypomineralization of permanent teeth 41%
[5] Ear-nose-throat abnormalities Hearing loss 33–39%
c.967_977dup AACCCCGTGGC C-terminal Thymic hypoplasia

Postaxial polydactyly of the right fifth toe		 No [4038]   Otitis media with effusion 2%
c.1158_1159delinsT C-terminal Hypoparathyroidism and hypocalcemia   Tracheomalacia/laryngomalacia 2%


  Laryngeal web 1%
Ocular abnormalities Hooding of the upper lid 41%
  Ptosis 9%
  Hooding of the lower lid 6%
  Epicanthal folds 3%
  Distichiasis 3%
Cranial base anomalies Platybasia 50–91%
  Basilar impression 3%
Cervical spine anomalies Atlas (C1) anomalies 75%
  Axis (C2) anomalies 59%
  Fusion of C2–C3 34%
Data were summarized from the following references: [16][17][18][19][20][21][22].
Table 2. Craniofacial and skeletal phenotypes of DGS/VCFS and Tbx1-null mice.
  DGS/VCFS Tbx1-Null Mice
Cranium Dolichocephaly Small cranium
  Abnormal skull morphology Hypoplastic parietal bone
  Malar flattening Hypoplastic interparietal bone
  Long face Unfused cranial sutures between frontal and parietal bones
    Temporal bone hypoplasia
    Absent zygomatic arch
    Abnormal zygomatic arch morphology
Cranial Base Platybasia Abnormal fusion of the basioccipital and basisphenoid bones
  Basilar impression Abnormal presphenoid bone morphology
    Abnormal basioccipital bone morphology
Palate Cleft palate Cleft palate
Facial asymmetry

Deafness Yes [4139]
c.1223delC C-terminal Conotruncal anomaly face syndrome

Velocardiofacial syndrome		 Yes [5]
c.1253delA C-terminal DiGeorge syndrome Yes [4240]
c.1320-1342del23bp C-terminal Velocardiofacial syndrome Yes/No [4341]
c.1399-1428dup30 C-terminal Tetralogy of Fallot

Scoliosis

Facial asymmetry

Upslanting palpebral fissures

Absent pulmonary valve

Isolated left pulmonary artery		 Yes [4442]
ClinVar (https://www.ncbi.nlm.nih.gov/clinvar accessed on 3 August 2021).

3.2. DiGeorge Syndrome Critical Region (DGCR)

DGCR8, DGCR6, and DGCR6L map to the commonly deleted 1.5 Mb region in DGS/VCFS (Figure 1). DGCR8 is a nuclear miRNA-binding protein required for miRNA biogenesis. Dgcr8 haploinsufficiency in mice reduces the expression of miRNAs in the brain [4543]. DGCR6 and DGCR6L genes encode a protein with a sequence similar to the Drosophila gonadal [4644]. In a chicken model, targeting DGCR6 function resulted in a vascular phenotype [4745]. Attenuation of DGCR6 affects the expression of three genes localized within the 1.5 Mb region, upregulating the expression of TBX1 and UFD1 and reducing the expression of HIRA in the heart and pharyngeal arches of the chicken embryos [4745]. Thus, the haploinsufficiency of DGCR8 or DGCR6 may be linked to DGS/VCFS phenotypes when targeting DGS/VCFS-related genes and miRNAs.

3.3. MicroRNAs

The deleted 1.5 Mb on the 22q11.2 locus includes several miRNAs, such as miR-185, miR-4716, miR-3618, miR-1286, miR-1306, and miR-6816 (Figure 1). The TargetScan miRNA target prediction program (http://www.targetscan.org accessed on 3 August 2021) identified that the 3′ UTR of TBX1 includes conserved sites for miR-183-5p, miR-96-5p, miR-1271-5p, miR-182-5p, miR-144-3p, miR-139-5p, miR-101-3p, and miR-451. Two miRNAs were confirmed to target the 3′ UTR of TBX1. miR-96-5p represses Tbx1 expression and, in turn, TBX1 suppresses the promoter activity and expression of miR-96 [4846]. miR-451a, a tumor suppressor, also directly targets TBX1 [4947]. The expression of this gene is upregulated in cutaneous basal cell carcinoma, inversely to miR-451a [4947]. miR-17-92 fine-tunes the expression of Tbx1 in craniofacial development, suggesting miR-17-92 as a candidate genetic modifier for Tbx1 [5048]. Thus, miRNAs both inside and outside the 22q11.2 locus may influence the severity of the clinical phenotypes of DGS/VCFS.

4. Current Insightaniofacial Phenotypes of DGS/VCFS Mouse Models

ThMouse penetrance and severity of congenital anomalies are related to genetic and environmental factors. Recent studies have revealed the function of TBX1 and models with DGS/VCFS help identify additional candidate genes or modifier genes that impact the severity and nfluence the penetrance of DGS/VCFS. Studiesand/or severity of DGS/VCFS mouse models have provided insights into signaling pathways and genes that interact with TBX1-related phenotypes. According to the mouse genome informatics (MGI) database (http://www.informatics.jax.org anccessed/or affect the on 3 August 2021), DGS/VCFS phenotypes. In addition, mouse models with DGS/VCFS may help the researchers to identify additional DGS/VCFS-related-related anomalies concerning Tbx1, Chrd, Tgfbr2, Vegfa, Fgf8, Crkl, Aldh1a2/Raldh2, Hoxa3, Kat6a/Moz/Myst3, Dicer1, Plxnd1, Dock1, Ndst1, Prickle1, Trappc10, Zfp366, and Foxn1 have been reported in genetically altered mice (Table 4). pWhenotypes. For example, there is potential to examine the phenotypes of these genes were analyzed according to biological process, “heart morphogenesis” and “cranial synchondroses, cranium, zygomatkeletal system development” were enriched. Our enrichment analysis using ToppCluster [49] indic arches, and pharyngeal muscles inated that genes associated with DGS/VCFS patients. The researchers also noted that ihenotypes in mice are specifically enriched in the morphogenesis of craniofacial tissues and heart (Figure 2A). Infotermation about ocular phenotypes inestingly, among these genes, only Tbx1-mut antd Chrd were specifically menrice is limited, although theshed in the morphogenesis of cricoid and thyroid cartilages (Figure 2A). Ge anomalies in patientses associated with DGS/VCFS have been reporphenotypes in mice also indicated [16][17].that DGS/VCrosstalk with key embryonicFS-related phenotypes involve the interaction of several signals, especiallying pathways, including bone morphogenetic protein (BMP), transforming growth factor (TGF)β, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), Rand retinoic Acid, and Sonic Hedgehog (SHH), critically regulates DGS/VCFS-related pharyngeal developmentacid signaling pathways (Figure 2B). Genes involved in these signalinggenetic pathways may modify of theTbx1 phenotypic spectrum of DGS/VCFS. Given the broad spectrum of DGS/VCFS disease phenotypes, other genes essential to craniofacial development could modify the phenotypic spectrum. Genetically engineered mice are useful for studying disease re likely to induce phenotypes; however, ablation of essential genes involved in cardiovascular similar to developmeTbx1-nt may cause early embryonic lethalityll mice (Figure 2B, whichTable 4). would prevent observation of craniofacial pThenotypes. For example, ablation of Ufd1, whose human ose artholog has been mapped to the 1.5 Mb region, causes early embryonic lethality before organogenesis in mice described below.
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Figure 2. Interaction network of genes associated with DGS/VCFS phenotypes in mice. (A) A gene-based network where each gene connects to a feature. The network was constructed using ToppCluster (https://toppcluster.cchmc.org/ accessed on 6 May 2022). Mouse phenotypes are shown in the network. (B) The protein–protein interaction network was constructed using the STRING tool (https://string-db.org/ accessed on 6 May 2022). Genes associated with DGS/VCFS phenotypes in mice (Table 4) were the input. Different colors represent different types of evidence of a connection between proteins.
Table 4. Craniofacial phenotypes of DGS/VCFS mouse model.
Gene SymbolInduced Mutation TypeCraniumPalateTeethMusclesEar-Nose-ThroatHyoid BonesCardio-Vascular
Tbx1NullYesYesYesYesYesYesYes
ChrdNullYesYesnrnrYesYesYes
Tgfbr2Deletion (Wnt1-Cre)YesYesnrnrnrnrYes
VegfaNullYesYesYesnrnrnrYes
Fgf8Hypomorphic alleleYesYesYesnrYesYesYes
CrklNullYesnrnrnrYesnrYes
Aldh1a2Hypomorphic allelenrnrnrnrYesYesYes
Hoxa3NullnrYesnrYesYesYesYes
Kat6aNullnrYesnrnrYesnrYes
Dicer1Deletion (Wnt1-Cre)YesnrnrnrnrnrYes
Plxnd1Single point mutationnrYesnrnrYesnrYes   Submucous cleft palate Submucous cleft palate
Dock1UndefinednrnrnrnrYesnrYes   Bifid uvula Bifid uvula
Ndst1Single point mutationnrnrnrnrYesnrYes   Highly arched palate  
Prickle1Single point mutationYesYesnrnrYesnrYes   Velopharyngeal insufficiency  
Trappc10UndefinedYesYesnrnrnrnrYes Mandible Retrognathia Absent mandibular coronoid process
Zfp366Single point mutationnrnrnrnrYesnrYes   Short mandible Short mandible
Foxn1Intragenic deletionnrnrnrnrYesnrYes   Micrognathia Micrognathia
Teeth Enamel hypoplasia Abnormal upper incisor morphology
  Single central incisor Absent upper incisors
  Small teeth  
  Abnormality of the dentition  
  Carious teeth  
Muscles Pharyngeal hypotonia Absent masseter muscle
    Absent pterygoid muscle
    Absent temporalis muscle
Eyes Hypertelorism/telecanthus Hypertelorism
  Downslanted palpebral fissures  
  Proptosis  
  Strabismus  
  Abnormal eyelid morphology  
  Epicanthus  
  Microphthalmia  
External Ears Small earlobe Ear lobe hypoplasia
  Low-set ears Lowered ear position
  Abnormally folded pinna Abnormal ear shape
  Preauricular pit Absent outer ear
    Anotia
Middle and Inner Ears Chronic otitis media Abnormal middle ear ossicle morphology
  Conductive hearing loss Absent middle ear ossicles
  Sensorineural hearing loss Abnormal stapes morphology
  Auditory canal stenosis Abnormal incus morphology
  Pulsatile tympanic membrane Abnormal malleus morphology
  Thickened tympanic membrane Absent stapes
  Tympanic membrane retraction Abnormal external auditory canal morphology
    Decreased tympanic ring size
Nose Prominent nasal bridge Short snout
  Abnormal nasal morphology  
  Underdeveloped nasal alae  
  Choanal atresia  
Throat Abnormal thorax morphology Small thyroid cartilage
  Abnormality of the pharynx Small cricoid cartilage
    Abnormal thyroid cartilage morphology
    Pharynx hypoplasia
Hyoid bones Delayed development of the hyoid bone Hyoid bone hypoplasia
  Invisible hyoid ossification center Abnormal hyoid bone morphology
Cervical spine Dysmorphic C1 Abnormal cervical atlas (C1) morphology
  Anterior arch cleft of C1 Absent arcus anterior of C1
  Open posterior arch C1  
  Fusion of C1–C2  
  Fusion of C2–C3  
  Upswept C2 lamina  
  Platyspondyly  
Others   Short clavicle
References [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] [6][7][8][9][10][2927][3028][3129][3230][3331][3432][3533][3634]
Data were summarized from the following references [6][7][8][9][10][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36], OMIM (https://www.omim.org accessed on 3 August 2021) and the Monarch Initiative (https://monarchinitiative.org accessed on 3 August 2021).
In addition to morphological anomalies, infants and young children with DGS/VCFS often exhibit a high prevalence of functional difficulties in feeding and speech/language associated with cleft palate, laryngeal anomalies, and velopharyngeal dysfunction [3735]. Even after cleft palate closure, children with DGS/VCFS sometimes present communication disorders related to speech-language problems, such as articulation disorders of speech sounds and vocal disorders [3735]. They exhibit slower language acquisition than those with other disorders that may be associated with abnormal muscle development.

3. Genetics of DGS/VCFS

DGS/VCFS is caused by a 1.5 to 2.5 Mb hemizygous deletion of chromosome 22q11.2 (Figure 1). Chromosomal microdeletions at 10p14-p13 (the DGS2 locus) in patients with DGS/VCFS phenotypes are defined as the DGS/VCFS complex 2. The researchers here focus on the 22q11.2 locus, its associated genes, and miRNAs.
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Figure 1. Proximal deletions of chromosome 22q11.2 are responsible for the clinical features of DGS/VCFS. Snapshot of the UCSC Genome Browser (http://genome.ucsc.edu accessed on 3 August 2021) in the hg38 assembly showing the genomic context in the proximal deletions of chromosome 22q11.2. Top, the 25 kb resolution Hi-C data in H1 human embryonic stem cell line (H1-hESC). Bottom, the coding (blue) and noncoding RNAs (green), including miRNAs and long noncoding RNAs, are shown.
Most of the chromosomal deletions of the 22q11.2 locus are de novo, but inherited deletions of the 22q11.2 locus have been reported in 6–28% of patients as autosomal dominant [16][17]. The majority of clinical phenotypes of DGS/VCFS are caused by proximal 1.5 Mb microdeletions [3][2220], resulting in a hemizygosity of approximately 30 coding genes, including DGCR6, PRODH, DGCR2, ESS2, TSSK2, GSC2, FAM246C, SLC25A1, CLTCL1, UFD1, HIRA, CDC45, MRPL40, C22orf39, CLDN5, TBX1, SEPTIN5, SEPT5-GP1BB, GP1BB, GNB1L, RTL10, TXNRD2, COMT, ARVCF, TANGO2, TRMT2A, RANBP1, CCDC188, DGCR8, ZDHHC8, RTN4R, DGCR6L, and C007326, as well as microRNAs (miRNAs) and long noncoding RNAs (Figure 1). The Hi-C chromatin structure of the 1.5 Mb region indicates interactions between these loci and their neighboring regions (Figure 1).

3.1. TBX1 Gene

The proximal deletion of 1.5 Mb on the 22q11.2 locus includes TBX1 (Figure 1). TBX1 is considered a candidate gene of DGS/VCFS because haploinsufficiency of TBX1 leads to the typical phenotypes of DGS/VCFS, conotruncal anomaly face syndrome (OMIM #217095), and tetralogy of Fallot (OMIM #187500) (Table 3). Identical mutations in TBX1 present among patients resulted in distinct phenotypes, suggesting that genetic and epigenetic changes or environmental factors are involved in the clinical phenotypes [5]. Further investigation is required to confirm that the variants cause DGS/VCFS and how they impact the phenotypes.
Table 3. DGS/VCFS-associated variants of TBX1.
Mutation Domain Condition Craniofacial Anomalies References
c.89_284del N-terminal DiGeorge syndrome Yes ClinVar Variant: 971780
c.199_224del N-terminal DiGeorge syndrome Yes ClinVar Variant: 949172
c.292A>T N-terminal DiGeorge syndrome Yes ClinVar Variant: 526036
c.385G>A T-box Tetralogy of Fallot No ClinVar Variant: 488618
c.443T>A (F148Y) T-box Conotruncal anomaly face syndrome Yes [5]
c.503T>C T-box DiGeorge syndrome

Velocardiofacial syndrome

(Shprintzen syndrome)

Tetralogy of Fallot		 Yes ClinVar Variant: 973222
c.569C > A (P190Q) T-box Congenital heart defects No [3836]
c.582C>G (H194Q) T-box Velocardiofacial syndrome Yes [3937]
c.928G>A (G310S) C-terminal DiGeorge syndrome Yes
Mouse models of DiGeorge syndrome with phenotypic similarity to human diseases can be found in the Mouse Genome Informatics (MGI) database (http://www.informatics.jax.org accessed on 3 August 2021). Data were summarized from the following references [6][7][8][9][10][29][30][31][32][33][34][35][36][50][51]. It is also essential to identify novel proteins that interact with TBX1 and examine whether interacting partners may influence the phenotypes of mouse models.[52][53][54][55][56][57][58][59]. nr, not reported.

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