Download 22q11.2 deletion and other Microdeletion Syndromes

22q11.2 deletion and other
Microdeletion Syndromes
Michael A. Kayser, D.O., FACMG
Director of Medical Services
Cancer Treatment Centers of America at Southwestern
Regional Medical Center
Tulsa, OK
Objectives
• Introduction to Genetics and field of
Medical Genetics
• Overview of Cytogenetics and
Chromosomal Microdeletions
• Detailed overview and description of
22q11.2 microdeletion Syndrome
Field of Medical Genetics
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Modern science of genetics, began
with the work of Gregor Mendel in the
mid-1800s
James D. Watson and Francis Crick
resolved the structure of DNA in 1953
Human Genome Project completion –
April 2003
Clinical Genetics
– Prenatal, Adult, Cancer, Pediatric,
Metabolic Disorders
Genetic Testing
– 1. Cytogenetics- chromosomes
– 2. Molecular Genetics - genes
– 3. Biochemical Genetics –
enzymes/metabolites
Cytogenetics
• Cytogenetics specializes in the study of cellular aspects of
heredity, particularly chromosomes
• Modern cytogenetics began in 1956 with the discovery that
normal human cells contain 46 chromosomes (Tjio and
Levan)
• In 1959 Lejeune discovered patients with Down syndrome
had an extra copy of chromosome 21
• In the late 1960's Caspersson developed banding
techniques
• In the 1980’s advances were made in molecular
cytogenetics- fluorescent in situ hybridization (FISH)
• In the 1990’s- Comparative genomic hybridization (CGH)molecular-cytogenetic method for the analysis of copy
number changes (gains /losses) in the DNA
Human chromosomes
22 pairs of autosomes + 2 sex chromosomes (XX or XY)
FISH and SKY
Comparative genome
hybridization array
Alteration in DNA Copy Number:
amplification and deletion
• Abnormal quantity of appearance of a genomic
region in the genome.
• Size: single gene - whole chromosome
• Abnormality: deletion – amplification
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Some variations among normal individuals
Can cause defects in human development
Contributors to cancer
Can effect function and gene expression
Microdeletions/duplications
Chromosome 22q11.2
deletion syndrome
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DiGeorge syndrome
Velocardiofacial syndrome
Conotruncal anomaly face
Some CHARGE
The majority of patients with DiGeorge syndrome, VCFS, CTAF have
hemizygous deletions of chromosome 22q11.2. The nomenclature is
not synonymous.
The Phenotype of Chromosome
22q11.2 Deletion Syndrome
• Cardiac anomaly 75%
– TOF 20%
– IAA 15%
– Truncus arteriosus 8%
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Palatal anomaly 69-100%
Hypocalcemia 17-60%
Speech delay 75%
Renal anomaly 36-37%
Skeletal anomaly 17-19%
Immunodeficiency 60-77%
Where to look for the deletion?
Cardiac Diseases
Any cardiac lesion
Interrupted aortic arch
Pulmonary atresia
Aberrant subclavian
Tetralogy of Fallot
1.1%
50-60%
33-45%
25%
11-17%
The Phenotype of Chromosome
22q11.2 Deletion Syndrome
• Cardiac anomaly 75%
– TOF 20%
– IAA 15%
– Truncus arteriosus 8%
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Palatal anomaly 69-100%
Hypocalcemia 17-60%
Speech delay 75%
Renal anomaly 36-37%
Skeletal anomaly 17-19%
Immunodeficiency 60-77%
Where to look for the deletion?
Velopharyngeal insufficiency following adnoidectomy
Isolated velopharyngeal insufficiency
Neonatal hypocalcemia
Schizophrenia
64%
37%
74%
0.3-6.4%
Any other clues?
• Speech delay is almost universal if you do
formal testing - 75% have obvious delay by
the rapid Denver developmental exam
• Dysmorphic facies
The diagnosis is established by FISH
22 well-characterized genes
Human Ch22q11.2
Centromere
DGCR6
IDD/DGCR2
TSK/DGS-G
ES2/DGS1
GSCL (Goosecoid-like homeobox gene)
CTP (Citrate transporter)
HIRA (transcription factor)
UFD1L (Ubiquitination degradation)
CDC45L
TMVCF
CDCrel-1
GP1b (Platelet glycoprotein)
TBX-1 (T-box transcription factor)
T10
COMT (Catechol-O-methyltransferase)
ARVCF
RANBP1
ZNF74
LZTR-1 (Transcription factor)
Heparin cofactor
CRKL
CLTCL
90% 8%
The significance of establishing the
diagnosis
• Toddlers
– 79% significant motor delay
– 53% significant expressive delay
– 26% significant receptive delay
• School-age
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12.7% average IQ (Weschler)
25.5% low average
34.5% borderline
27.3% retarded
Behavior/School issues
• 65.5% have a nonverbal learning disability
• 25% have ADHD
• 6-30% will develop schizophrenia
The Immunodeficiency of Chromosome
22q11.2 Deletion Syndrome
• 60-77% of patients have laboratory
evidence of quantitative T cell defects
• Only 0.5-1.0% have absent T cells
• T cell proliferation is usually normal
• 2-4% are IgA deficient
• 10% have delayed production of IgG
Clinical Immunodeficiency
7% of all ages have significant, serious infections
9% have autoimmune disease
Older children and adults continue to get infections
27% recurrent sinusitis
25% recurrent otitis media
7% recurrent bronchitis
4% recurrent pneumonia
Autoimmunity
• JRA is seen 20X more frequently (2%)
• ITP is seen 200X more frequently (4%)
• AHA, IBD are seen in about 1%
• Older patients develop autoimmune diseases of
adults
Objectives
• Introduction to Genetics and field of
Medical Genetics
• Overview of Cytogenetics and
Chromosomal Microdeletions
• Detailed overview and description of
22q11.2 microdeletion Syndrome
Questions?