Clinical Summary

Clinical Summary

Clinical Diagnosis

Testing

Molecular Genetic Testing

Testing Strategy

Genetically Related (Allelic) Disorders

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Clinical Diagnosis

The diagnosis of the 22q11.2 deletion syndrome is suspected in individuals with a range of findings that may include some combination of the following:

  • Congenital heart disease (particularly conotruncal malformations) don’t think parents will know what this is maybe go with most frequent as a list (such as: tetralogy of Fallot, VSD, interrupted aortic arch, truncus arteriosus, vascular ring, ASD)
  • Palatal abnormalities (likewise –would suggest for example cleft plate, cleft lip and palate, bifid uvula or most often velopharyngeal insufficiency/dysfunction (VPI/VPD)
  • Trouble fighting infection (Immune deficiency)
  • Low calcium (Hypocalcemia)
  • Feeding and swallowing problems
  • Kidney differences (renal agenesis, hydronephrosis, multicystic/dysplastic kidneys, duplicated kidney, horseshoe kidney)
  • Learning difficulties
  • Differences in attention (ADHD/ADD)
  • Differences in behavior (anxiety)

Less frequent associations include:

  • Growth hormone deficiency
  • Autoimmune disease (thrombocytopenia, juvenile rheumatoid arthritis, Grave’s disease, vitiligo, neutropenia, hemolytic anemia)
  • Hearing loss (sensorineural and conductive), abnormalities of the inner and outer ear (preauricular pits and tags, microtia, cochlear differences)
  • Psychiatric illness

Other structural anomalies:

  • Bony differences: differences in the bones of the neck and spine (vertebral differences), extra fingers/toes (pre and postaxial polydactyly of the hands and postaxial polydactyly of the feet), extra ribs, differences in the wing bones (scapula), club foot, premature fusion of the bones of the skull (craniosynostosis)
  • Genitourinary tract anomalies: Hernia (umbilical and inguinal) absent uterus, hypospadias, and undescended testes
  • Abnormalities of the airway (Laryngotrachealesophageal differences including problems with the windpipe (trachea) and feeding tube (esophagus) including a vascular ring, laryngeal web, trachealesophageal fistula, esophageal atresia, tracheal atresia
  • Eye findings (tortuous retinal vessels, ptosis, posterior embryotoxin, scleracornea, coloboma, cataract, and strabismus)
  • Differences in the brain and spinal cord (CNS) (cerebellar atrophy, polymicrogyria, enlarged sylvian fissures, neural tube defects, tethered cord, unprovoked seizures, and asymmetric crying facies)
  • Gastrointestinal anomalies (GI) (anteriorly placed anus or imperforate anus, esophageal atresia, jejunal atresia, accessory spleens, umbilical hernia, diaphragmatic hernia, intestinal malrotation, and Hirshprung disease

Rare Malignancies:

  • Hepatoblastoma, renal cell carcinoma, Wilm’s tumor, neuroblastoma, thyroid carcinoma, melanoma, leukemia
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Testing

Cytogenetic testing. A small percentage (<1%) of individuals with clinical findings of the 22q11.2 deletion syndrome have chromosomal rearrangements involving 22q11.2, such as a translocation between chromosome 22 and another chromosome.

Fish testing will identify ~85% of deletions; the remaining ~15 of deletions require other testing such as MLPA, comparative genomic hybridization (CGH) or SNP microarray testing

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Molecular Genetic Testing

Genetic Testing

Clinical testing

  • In 1982, only chromosome studies could identify 22q11.2 deletions by looking at them under the microscope
  • In 1991 FISH (fluorescence in situ hybridization) probes were developed that detect ~86% pf deletions
      • The two probes commercially available for 22q11.2 FISH analysis are TUPLE1 and N25
      • The detection rate of FISH analysis using either probe is thought to be equivalent; however, FISH using either one of these probes is not sensitive enough to detect smaller deletions (<40 kb) within 22q11.2.
  • Newer and more precise tests include MLPA (Multiplex ligation-dependent probe amplification), CGH (comparative genomic hybridization), and SNP microarrays
      • These tests are useful because they identify small deletions that would be missed by FISH
      • They identify 22q11.2 duplications
      • CGH and microarrays do not require an elevated index of suspicion of the deletion or duplication

Gene. The 22q11.2 results in ~50 genes missing in the region. [Driscoll et al 1992, Wilson et al 1992, Desmaze et al 1993, Driscoll et al 1993]. This sets up a blueprint for the body to form affecting cells derived from the neural crest often resulting in the birth defects outlined above. Important genes identified thus far in the region include: TBX1, COMT, SCARF2, SNAP29, PRODH, Pl4KA, GPIbβ and CRKL1.

Clinical uses

  • Confirmatory diagnostic testing
  • Parental testing
  • Prenatal diagnosis

Research testing. A few individuals with findings of the 22q11.2 deletion syndrome have normal routine cytogenetic studies and no deletion by FISH, MLPA, CGH or microarray. These individuals may have a change in a gene within the regions, such as TBX1, or a different condition such as CHARGE syndrome.

 

Table 1. Testing Used in 22q11.2 Deletion Syndrome

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Testing Strategy

When a deletion 22q11.2 is suspected, it is recommended that routine cytogenetic analysis be performed at the time of FISH/MLPA/CGH/array testing because a small percentage (<1%) of individuals with clinical findings of the 22q11.2 deletion syndrome have chromosomal rearrangements involving 22q11.2, such as a translocation between chromosome 22 and another chromosome.

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Genetically Related (Allelic) Disorders

No other phenotypes are associated with deletion of 22q11.2.

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