Tipping the Scales: Imbalances in Our Chromosomes

April 28th, 2021

Elizabeth Mizerik, CGCLaurie 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?

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/fulltextElizabeth Mizerik, CGC

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 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

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

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/condition/williams-syndrome/

Williams Syndrome

Deletion of 7q11.2

http://www.pitt.edu/~super1/lecture/lec45851/019.htm

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

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

• 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

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

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/

http://www.nsgc.org/page/find-a-gc-searchElizabeth Mizerik, CGC

https://www.acmg.netElizabeth Mizerik, CGC

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

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