Chromosome 22q11.2 Deletion Syndrome

DiGeorge Syndrome

Velocardiofacial Syndrome

Conotruncal Anomaly Facial Syndrome

 

 

Epidemiology and Etiology:

    • 1:4000 births – most common human site of deletion
    • Del(22)(q11.2q11.2)
    • NAHR at LCRs most common mechanism
    • Failure of development of the 3rd and 4th pharyngeal pouches
      • Motor cortex development may be involved
    • De novo usually (94%)
    • Inherited (6%) (AD)
      • Variable expressivity
      • Parent may be asymptomatic carrier or with very low expressivity
      • Even most monozygous twins are discordant

 

Common sites:

    •  

 

Gross features:

    • (variable clinical features)
    • CATCH 22 (mnemonic)
      • Congenital heart defects
        • outflow tract malformations
        • > 40% of patients with tetralogy of Fallot AND pulmonary atresia have this microdeletion
        • > 60% of patients with tetralogy of Fallot AND absent pulmonary valve have this microdeletion
      • (Abnormal) facial dysmorphisms
        • prominent nose
        • retrognathia
      • Thymic hypoplasia
      • Cleft palate
        • palate abnormalities
      • Hypoparathyroidism
        • Parathyroid hypoplasia

 

Histologic features:

    •  

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 

 

 

 

Molecular features:

    • small deletion of band 11.2 on the long arm of chromosome 22
      • detection of deletion by FISH (TUPLE1 / HIRA)
      • larger deletions are visible on G-banding (look for the first G-positive band past the centromere)
      • 3 major breakpoints:
        • LCR2 (17 Mb)
          • common proximal breakpoint
          • also common breakpoint for duplication
          • also breakpoint for type I CES
        • LCR3a (18.75 Mb)
          • 1.5 Mb deletion breakpoint
          • Also recurrent constitutional t(11;22) breakpoint
          • Also recurrent constitutional t(17;22) breakpoint
          • Other non-recurrent translocations occur here
        • LCR4 (20 Mb)
          • 3 Mb deletion breakpoint
          • Also 3 Mb duplication breakpoint
          • Type II CES duplication breakpoint
        • Note:
    • molecular basis is unknown – many genes are deleted
      • TBX-1 is thought to play a major role
        • Transcription factor involved in the development of the pharyngeal system (T-gene transcription factor)
      • CRKL is likely a modifier of the syndrome
      • YPEL1 is a candidate
        • Nuclear protein
      • Size of deletion does not generally correlate with phenotype
      • Epigenetic “second hit” may be required (speculation)

 

Other features:

    • 2 previously separate but partially overlapping clinical syndromes are associated with this deletion:
      • DiGeorge syndrome
      • Velocardiofacial syndrome
    • variable clinical features, so the syndrome is often missed
      • intellectual disability (92%)
        • developmental delay
      • psychotic disorders (58%)
        • schizophrenia
        • poor social function (may be only symptom in some carriers)
        • others
      • T-cell immunodeficiency
        • Low levels of circulating T lymphocytes
        • Susceptibility to certain fungal and viral infections
      • Hypocalcemia
        • Tetany
      • Motor neurological dysfunction – drooling, abnormal speech, dysphagia

 

References:

·         Gardner RJM, Sutherland GR. Chromosome abnormalities and genetic counseling. Oxford University Press; 2004.

·         Torres-Juan  et al. BMC Medical Genetics 2007 8:14   doi:10.1186/1471-2350-8-14