Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 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% • • • • • • 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 – – – – 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?