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 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 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 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% Palatal anomaly % Hypocalcemia 17-60% Speech delay 75% Renal anomaly 36-37% Skeletal anomaly 17-19% Immunodeficiency 60-77%

Where to look for the deletion? Any cardiac lesion1.1% Interrupted aortic arch50-60% Pulmonary atresia33-45% Aberrant subclavian25% Tetralogy of Fallot11-17% Cardiac Diseases

The Phenotype of Chromosome 22q11.2 Deletion Syndrome Cardiac anomaly 75% –TOF 20% –IAA 15% –Truncus arteriosus 8% Palatal anomaly % 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 adnoidectomy64% Isolated velopharyngeal insufficiency 37% Neonatal hypocalcemia74% Schizophrenia %

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

The significance of establishing the diagnosis Toddlers –79% significant motor delay –53% significant expressive delay –26% significant receptive delay School-age –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 % 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?