tipping the scales: imbalances in our chromosomes07d0901f-86b6-4cd0-b7a2... · 2021. 5. 4. ·...
TRANSCRIPT
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Tipping the Scales: Imbalances in Our Chromosomes
April 28th, 2021
Elizabeth Mizerik, CGCLaurie Robak, MD, PhD
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Outline• Overview of DNA/chromosomes
• Overview of chromosomal microarray (CMA)
• Specific syndromes• 22q11.2 deletion syndrome (DiGeorge syndrome)• 1p36 deletion syndrome• Williams syndrome
• Absence of heterozygosity: social/ethical implications for families
• Genetics resources
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Chromosomes • Humans have 46 chromosomes• 22 paired autosomes + paired sex chromosomes• 23 maternal, 23 paternal
Males: 46, XY*Females: 46, XX*
*There are exceptions
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Chromosomes
Elizabeth Mizerik, CGC
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Chromosomal Microarray Analysis (CMA)
• A CMA is a genetic test that looks for extra or missing pieces of genetic information.
• If you think about our genetic information as the body’s instruction manual, having extra or missing instructions can make the body not develop or function how we would expect.
• Eg. Down syndrome
• These extra or missing pieces are called “copy number variants” or “microdeletion/microduplication syndromes”
Elizabeth Mizerik, CGC
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How does a CMA work?
https://www.ajog.org/article/S0002-9378(16)30450-1/fulltext
Elizabeth Mizerik, CGC
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Elizabeth Mizerik, CGC
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https://www.fertstert.org/article/S0015-0282(18)30005-0/fulltextElizabeth Mizerik, CGC
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Indications for CMA
• Autism spectrum disorder, developmental delays, or intellectual disability
• Multiple congenital anomalies• Heart defects• Often the first line test for genetics evaluation
Elizabeth Mizerik, CGC
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Potential health problems associated with CMA abnormalitiesThere are MANY health problems may be associated with copy number variants
Examples:• Congenital heart disease• Developmental delay / intellectual disability• Structural brain abnormalities• Kidney abnormalities• Changes to a child’s facial features (eg. Down syndrome)
• Also be aware that if a child has a chromosomal deletion or duplication, the parent may also have the same deletion or duplication
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22q11.2 deletion syndrome
• Also known as DiGeorge syndrome or Velovardiofacial syndrome• Clinical features
• Congenital heart disease (74%)• Tetralogy of Fallot (20%)
• Distinct facies• Immune deficiency (77%)• Palate abnormalities (69%)
• Velopharyngeal incompetence- VPI (27%)• Cleft lip and/ or palate (2%)
• Hypocalcemia (50%)• Renal anomalies (30%)
Prevalence:1/3,800-6,000
Elizabeth Mizerik, CGC
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Elizabeth Mizerik, CGC
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1p36 deletion syndrome
Prevalence:1/5,000-10,000
Elizabeth Mizerik, CGC
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Elizabeth Mizerik, CGC
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Williams Syndrome Deletion of 7q11.2
Clinical features• Heart: supravalvular aortic stenosis (75%), can also have
peripheral pulmonic stenosis• Intellectual disability: mild• “Cocktail party personality”• Hypercalcemia• Distinctive facial features
• Wide mouth• Broad forehead with bitemporal narrowing• Widely-spaced teeth• Small chin
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Williams Syndrome
https://medlineplus.gov/genetics/condition/williams-syndrome/
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Williams Syndrome
Deletion of 7q11.2
http://www.pitt.edu/~super1/lecture/lec45851/019.htm
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Potocki-Lupski Syndrome
• Duplication of 17p11.2• 1/20,000
Main features:• Hypotonia• Poor feeding/failure to thrive• Developmental delay/intellectual
disability• Autism spectrum disorders are
common
• Physical Features:• Short stature• High arched palate• Dental issues (malocclusion)• Broad forehead• Downslanting palpebral fissures• Long nasal tip• Micrognathia
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Potocki et al., AJHG, 2007
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Autism susceptibility loci
• Loci = location, eg. region on a chromosome
• There are certain copy number changes that predispose children to having autism but don’t necessarily cause other health problems
• Examples:• chromosome 15q11-q13 duplication syndrome• chromosome 16p11.2 deletions and duplications – found in 1% of children
with autism
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Absence of heterozygosity
• Every person inherits pairs of chromosomes, one from mom and one from dad in each pair
• The sequence of DNA on the chromosomes should be different from each other
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Absence of heterozygosity
• At some locations on a chromosome, there will be places where people can have DNA changes that are common and do not cause disease. These are called single nucleotide polymorphisms (SNPs)
• By random chance, for each SNP, a person has a 25% chance to be A/A (homozygous), a 25% chance to be B/B (homozygous) and a 50% chance to be heterozygous (A/B)
• If a person is all A/A and B/B, and does not have any differences (A/B) at a SNP location, that is called absence of heterozygosity
A/A
A/B
B/B
•.•.
Schaaf et al., Ann Rev Hum Genet, 2011
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What does absence of heterozygosity mean for the patient?• It could mean that both copies of the chromosome were inherited
from one parent (uniparental disomy). There are certain genetic conditions associated with this.
• If seen on multiple chromosomes, it could mean parents are related.
• BOTH of these conditions increase the risk of autosomal recessive disorders.
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Implications of AOH on multiple chromosomes• What it can tell you:
• If parents are related• Degree of relationship (eg. 25% similar means father of baby is the mother’s father, brother
or son)
• What it can’t tell you:• Was the relationship consensual?• Who is the father? (or mother)?• If parents are related but do not know it (eg. adoption)
• If a baby has AOH on multiple chromosomes, you need to take a careful family history to determine if there is a possibility of abuse
• CMA alone only tells you parents are related, it does not identify who the parents are specifically
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Conclusions
• CMA detects small regions of chromosomes that are missing or added
• These deletions and duplications on chromosomes can cause specific genetic syndromes that can affect many parts of the body
• Chromosomal microdeletions and duplications can run in families
• CMA can also detect absence of heterozygosity, which may mean that parents are related
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Genetics Online Resources
• Genereviews: https://www.ncbi.nlm.nih.gov/books/NBK1116/• MedlinePlus Genetics: https://medlineplus.gov/genetics/
• Genetics and Rare Diseases Information Center (GARD): https://rarediseases.info.nih.gov/
• National Organization for Rare Disorders (NORD): rarediseases.org• Unique: rarechromo.org
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How to Find Local Genetics Services
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https://www.dshs.texas.gov/genetics/provider.shtm
Tx Dept of State Health Services
Elizabeth Mizerik, CGC
Also see:Mountain States Regional Genetics Network: https://www.mountainstatesgenetics.org/
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http://www.nsgc.org/page/find-a-gc-searchElizabeth Mizerik, CGC
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https://www.acmg.netElizabeth Mizerik, CGC
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How to Find Family Support GroupsThese groups are typically your best resource for staying up to date on new information known about a particular condition
Elizabeth Mizerik, CGC
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Syndrome-specific support groups• Google [syndrome name] + Support • Google [gene name] + Support• Search for the syndrome name or gene name on social
media • Search Facebook• Search hashtags on Twitter or Instagram (#noonansyndrome)
Elizabeth Mizerik, CGC
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Chromosome disorder support groups
• Unique chromosome (rarechromo.org) • Chromosome Disorder Outreach (chromodisorder.org)
Elizabeth Mizerik, CGC