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Chromosome 22q11 Deletion Syndromes

Chromosome 22q11 Deletion Syndromes. (aka Di George Syndrome, Velocardiofacial Syndrome, Shprintzen Syndrome, Conotruncal Anomaly Face Syndrome, CATCH 22). Chromosome 22q11.2 Deletion Syndrome. History Genetics Features. 1968. Di George. Conotruncal cardiac anomalies.

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Chromosome 22q11 Deletion Syndromes

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  1. Chromosome 22q11 Deletion Syndromes (aka Di George Syndrome, Velocardiofacial Syndrome, Shprintzen Syndrome, Conotruncal Anomaly Face Syndrome, CATCH 22)

  2. Chromosome 22q11.2 Deletion Syndrome • History • Genetics • Features

  3. 1968 Di George Conotruncal cardiac anomalies Parathyroid hypoplasia Thymic hypoplasia

  4. 1978 Shprintzen Cleft palate – velo Cardiac defects – cardio Similar facial appearance - facio

  5. Scambler Chromosome 22q11.2 deletion Cardiac defects Abnormal facies Thymic hypoplasia Cleft palate Hypocalcaemia 22deletion 1991

  6. Chromosomes

  7. DNA Structure

  8. Chromosome 22q11.2 Microdeletion 22q11.2

  9. Fluorescent In Situ Hybridisation (FISH) Normal Deleted

  10. Centromere Centromere 22q11.2

  11. Multiplex Ligation-dependent Probe Analysis (MLPA)

  12. Chromosome 22q11.2 Microdeletion 22q11.2

  13. CEN Chromosome 22q11.2 deletion HIRA/TUPLE1 NLVCF UFD1L CDC45L CLDN5 PNUTL1 CDCrel-1 GP1bb TBX1 COMT TR ARVCF T10 LAMC1/DGCR6 RANBP1 ZNF74 HCF2 PIK4CA SNAP29 CRKL LZTR1 P2RXL1 SLC7A4 DGCRS PRODH Y191g08 CALS2 DGCR3 IDD STK22A PRODH GSCL SLC25A1 DVL1L1 CLTCL1 MDGCR TDR

  14. DNA Structure

  15. LCR LCR LCR 1.5Mb < 5% 3Mb 90% 22q11.2 Deletion TEL CEN

  16. CEN LCR LCR CEN LCR LCR Mechanism

  17. CEN LCR LCR CEN LCR LCR Mechanism

  18. CEN LCR LCR CEN LCR LCR Mechanism CEN LCR LCR CEN LCR LCR

  19. CEN CEN LCR LCR LCR LCR CEN CEN LCR LCR LCR LCR Mechanism

  20. CEN CEN LCR LCR LCR LCR CEN CEN LCR LCR LCR LCR Mechanism

  21. CEN CEN LCR LCR LCR LCR CEN CEN LCR LCR LCR LCR Mechanism

  22. CEN CEN LCR LCR LCR LCR CEN CEN LCR LCR LCR LCR Mechanism

  23. CEN CEN LCR LCR LCR LCR CEN CEN LCR LCR LCR LCR Mechanism

  24. CEN CEN LCR LCR LCR LCR CEN LCR LCR Mechanism CEN LCR LCR + + CEN CEN LCR LCR LCR LCR 3Mb Duplication 3Mb Deletion

  25. LCR LCR Mechanism LCR

  26. LCR LCR Mechanism LCR LCR LCR LCR

  27. LCR LCR Mechanism LCR LCR LCR LCR

  28. LCR LCR Mechanism LCR LCR LCR LCR

  29. LCR LCR Mechanism LCR LCR LCR LCR

  30. LCR LCR Mechanism LCR LCR LCR LCR + CEN LCR LCR 3Mb Deletion

  31. Incidence • 1:4000 livebirths • M = F • 5-10% deletions inherited (mat>pat) • > 80 associated medical problems

  32. Major Features • Characteristic facial appearance 100% • Learning difficulties 70 – 90% • Congenital heart disease 74% • Immune deficiency 77% • Palatal problems 69% • Low calcium levels 50% • Kidney problems 30%

  33. Minor Features • Hearing loss (conductive and sensorineural) • Feeding problems • Laryngotracheoesophageal anomalies • Short stature (+/- GH deficiency) • Autoimmune disorders • Seizures • Skeletal problems

  34. Maxillary hypoplasia Bulbous nasal tip Myopathic facies Characteristic Facies Long face Hooded eyelids Prominent nasal root Short palpebral fissures

  35. Characteristic Facies ‘Squared off’ helix Small Overfolding

  36. CEN Chromosome 22q11.2 deletion HIRA/TUPLE1 NLVCF UFD1L CDC45L CLDN5 PNUTL1 CDCrel-1 GP1bb TBX1 COMT TR ARVCF T10 LAMC1/DGCR6 RANBP1 ZNF74 HCF2 PIK4CA SNAP29 CRKL LZTR1 P2RXL1 SLC7A4 DGCRS PRODH Y191g08 CALS2 DGCR3 IDD STK22A PRODH GSCL SLC25A1 DVL1L1 CLTCL1 MDGCR TDR

  37. TBX1 • > 20 T-box genes • Important for the development of organs of the developing baby during pregnancy • Alterations or absence can result in problems especially with the structure of the heart

  38. Cardiac Defects • Tetralogy of Fallot 22% • Interrupted aortic arch 15% • VSD 13% • Truncus arteriosus 7% • Vascular ring 5% • ASD 3% • Aortic arch anomaly 4% • VSD/ASD 4% • Other 4%

  39. Early Development Branchial arch/ Pharyngeal pouch Thymus Parathyroids Branchial arch arteries Face

  40. Immune Function Reduced cells of thymic lineage Improves with age Severe immunodeficiency is extremely rare • Impaired T-cell production 67% • Impaired T-cell function 19% • Humoral defects 23% • IgA deficiency 13%

  41. Parathyroid Function • Hypocalcaemia 30% • Often asymptomatic • Improves with age • Intermittent recurrences

  42. CEN Chromosome 22q11.2 deletion HIRA/TUPLE1 NLVCF UFD1L CDC45L CLDN5 PNUTL1 CDCrel-1 GP1bb TBX1 COMT TR ARVCF T10 LAMC1/DGCR6 RANBP1 ZNF74 HCF2 PIK4CA SNAP29 CRKL LZTR1 P2RXL1 SLC7A4 DGCRS PRODH Y191g08 CALS2 DGCR3 IDD STK22A PRODH GSCL SLC25A1 DVL1L1 CLTCL1 MDGCR TDR

  43. Autoimmune Disease • Juvenille rheumatoid arthritis • Idiopathic thrombocytopenia • Hyperthyroidism • Hypothyroidism • Vitiligo • Haemolytic anaemia • Coeliac disease

  44. Palate Abnormalities • Velopharyngeal Incompetence 27% • Submucosal cleft palate 16% • Overt cleft palate 11% • Bifid uvula 5% • Cleft lip +/- palate 2% • Infant feeding problems 8%

  45. Growth • 40% < 5th centile • GH deficiency more common than general population

  46. Kidney Problems • Single kidney • Echogenic kidneys • Multicystic/dysplastic kidneys • Small kidneys • Horseshoe kidneys • Calculi • Duplex collecting systems • Hydronephrosis • Renal Tubular Acidosis

  47. CNS/Development • Hypotonia in infancy • Seizures (hypocalcaemia) • Learning disability • Average IQ 75 (range 50-100) • Receptive/Expressive language delay • Verbal IQ > Performance IQ • Psychiatric problems in adulthood are more common than general population

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