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Chromosome 22q11 Deletion Syndromes
(aka Di George Syndrome, Velocardiofacial Syndrome, Shprintzen Syndrome, Conotruncal Anomaly Face Syndrome, CATCH 22)
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Chromosome 22q11.2 Deletion Syndrome
History Genetics Features
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1968 Di George Conotruncal cardiac anomalies Parathyroid hypoplasia
Thymic hypoplasia
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1978 Shprintzen Cleft palate – velo Cardiac defects – cardio
Similar facial appearance - facio
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1991 Cardiac defects Abnormal facies Thymic hypoplasia Cleft palate
Scambler Chromosome 22q11.2 deletion Cardiac defects Abnormal facies Thymic hypoplasia Cleft palate Hypocalcaemia 22 deletion
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Chromosomes
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DNA Structure
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Chromosome 22q11.2 Microdeletion
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Fluorescent In Situ Hybridisation (FISH)
Normal Deleted
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Centromere Centromere 22q11.2
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Multiplex Ligation-dependent Probe Analysis (MLPA)
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Chromosome 22q11.2 Microdeletion
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Chromosome 22q11.2 deletion TDR MDGCR CEN 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 CEN DGCRS PRODH Y191g08 CALS2 DGCR3 IDD STK22A GSCL SLC25A1 DVL1L1 CLTCL1 MDGCR TDR
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DNA Structure
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22q11.2 Deletion LCR LCR LCR TEL CEN 3Mb 90% 1.5Mb < 5%
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Mechanism CEN LCR CEN LCR
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Mechanism CEN LCR CEN LCR
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Mechanism CEN LCR CEN LCR CEN LCR
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Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
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Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
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Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
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Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
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Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
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Mechanism + + CEN LCR CEN LCR LCR CEN LCR CEN LCR CEN CEN LCR LCR LCR
3Mb Duplication 3Mb Deletion
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Mechanism LCR LCR
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Mechanism LCR LCR LCR LCR LCR
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Mechanism LCR LCR LCR LCR LCR
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Mechanism LCR LCR LCR LCR LCR
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Mechanism LCR LCR LCR LCR LCR
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Mechanism LCR LCR LCR LCR LCR + CEN LCR LCR 3Mb Deletion
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Incidence 1:4000 livebirths M = F
5-10% deletions inherited (mat>pat) > 80 associated medical problems
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Major Features Characteristic facial appearance 100%
Learning difficulties – 90% Congenital heart disease 74% Immune deficiency % Palatal problems % Low calcium levels % Kidney problems %
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Minor Features Hearing loss (conductive and sensorineural)
Feeding problems Laryngotracheoesophageal anomalies Short stature (+/- GH deficiency) Autoimmune disorders Seizures Skeletal problems
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Characteristic Facies
Long face Hooded eyelids Prominent nasal root Short palpebral fissures Maxillary hypoplasia Bulbous nasal tip Myopathic facies
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Characteristic Facies
‘Squared off’ helix Small Overfolding
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Chromosome 22q11.2 deletion TDR MDGCR CEN TBX1 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 CEN DGCRS PRODH Y191g08 CALS2 DGCR3 IDD STK22A GSCL SLC25A1 DVL1L1 CLTCL1 MDGCR TDR
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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
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Cardiac Defects Tetralogy of Fallot 22% Interrupted aortic arch 15%
VSD % Truncus arteriosus 7% Vascular ring 5% ASD % Aortic arch anomaly 4% VSD/ASD 4% Other %
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Early Development Branchial arch/ Pharyngeal pouch Thymus Parathyroids
Branchial arch arteries Face
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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%
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Parathyroid Function Hypocalcaemia 30% Often asymptomatic
Improves with age Intermittent recurrences
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Chromosome 22q11.2 deletion TDR MDGCR CEN COMT 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 CEN DGCRS PRODH Y191g08 CALS2 DGCR3 IDD STK22A GSCL SLC25A1 DVL1L1 CLTCL1 MDGCR TDR
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Autoimmune Disease Juvenille rheumatoid arthritis
Idiopathic thrombocytopenia Hyperthyroidism Hypothyroidism Vitiligo Haemolytic anaemia Coeliac disease
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Palate Abnormalities Velopharyngeal Incompetence 27%
Submucosal cleft palate 16% Overt cleft palate % Bifid uvula % Cleft lip +/- palate 2% Infant feeding problems 8%
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Growth 40% < 5th centile
GH deficiency more common than general population
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Kidney Problems Single kidney Echogenic kidneys
Multicystic/dysplastic kidneys Small kidneys Horseshoe kidneys Calculi Duplex collecting systems Hydronephrosis Renal Tubular Acidosis
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CNS/Development Hypotonia in infancy Seizures (hypocalcaemia)
Learning disability Average IQ 75 (range ) Receptive/Expressive language delay Verbal IQ > Performance IQ Psychiatric problems in adulthood are more common than general population
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