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Tipping the Scales: Imbalances in Our Chromosomes April 28Th, 2021

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Tipping the Scales: Imbalances in Our Chromosomes April 28Th, 2021 Tipping the Scales: Imbalances in Our Chromosomes April 28th, 2021 Elizabeth Mizerik, CGC Laurie Robak, MD, PhD 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 Elizabeth Mizerik, CGC Chromosomes • Humans have 46 chromosomes • 22 paired autosomes + paired sex chromosomes • 23 maternal, 23 paternal Males: 46, XY* Females: 46, XX* *There are exceptions Chromosomes Elizabeth Mizerik, CGC 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 How does a CMA work? Elizabeth Mizerik, CGC https://www.ajog.org/article/S0002-9378(16)30450-1/fulltext Elizabeth Mizerik, CGC Elizabeth Mizerik, CGC https://www.fertstert.org/article/S0015-0282(18)30005-0/fulltext 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 Potential health problems associated with CMA abnormalities There 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 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%) Prevalence: • Cleft lip and/ or palate (2%) 1/3,800-6,000 • Hypocalcemia (50%) • Renal anomalies (30%) Elizabeth Mizerik, CGC Elizabeth Mizerik, CGC 1p36 deletion syndrome Prevalence: 1/5,000-10,000 Elizabeth Mizerik, CGC Elizabeth Mizerik, CGC 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 Williams Syndrome https://medlineplus.gov/genetics/condi tion/williams-syndrome/ Williams Syndrome Deletion of 7q11.2 http://www.pitt.edu/~s uper1/lecture/lec4585 1/019.htm Potocki-Lupski Syndrome • Duplication of 17p11.2 • Physical Features: • 1/20,000 • Short stature • High arched palate • Dental issues (malocclusion) Main features: • Broad forehead • Hypotonia • Downslanting palpebral fissures • Long nasal tip • Poor feeding/failure to thrive • Micrognathia • Developmental delay/intellectual disability • Autism spectrum disorders are common Potocki et al., AJHG, 2007 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 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 •. •. Absence of heterozygosity A/A A/B B/B • 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 Schaaf et al., Ann Rev Hum Genet, 2011 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. 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 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 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 How to Find Local Genetics Services Tx Dept of State Health Services Also see: Mountain States Regional Genetics Network: https://www. mountainstatesgenetics. org/ Elizabeth Mizerik, CGC https://www.dshs.texas.gov/genetics/provider.shtm Elizabeth Mizerik, CGC http://www.nsgc.org/page/find-a-gc-search Elizabeth Mizerik, CGC https://www.acmg.net How to Find Family Support Groups These groups are typically your best resource for staying up to date on new information known about a particular condition Elizabeth Mizerik, CGC 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 Chromosome disorder support groups • Unique chromosome (rarechromo.org) • Chromosome Disorder Outreach (chromodisorder.org) Elizabeth Mizerik, CGC.
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