Genetics E1- Review

What symbol indicates an affected individual on a pedigree?

Shaded in shape

What symbol indicates a male on a pedigree?

Square

What symbol indicates a female on a pedigree?

Circle

What does an arrow indicate on a pedigree?

Proband

What does a horizontal line indicate on a pedigree?

Mating

What does a vertical line indicate on a pedigree?

Offspring

What do roman numerals mean on pedigrees?

Generations

What is the p-arm (“petit”)?

Shorter arm

What is the q-arm (“queue”)?

Longer arm

What divides the chromosomal arms?

Centromere

How are bands numbered?

From centromere outward

How do you read the following chromosome nomenclature: 15q11.2

Chromosome 15, q-arm, region 11, band 2

What is transcription?

DNA to mRNA

What is translation?

mRNA to protein

What are the DNA bases?

A, T, G, C

What are the RNA bases?

A, U, G, C

What type of substitution mutation results in no amino acid change?

Silent

What type of substitution mutation results in a different amino acid?

*ex- sickle cell

Missense

What type of substitution mutation results in a premature stop codon?

Nonsense

What is the most common type of mutation?

Substitution

What is an insertion or deletion mutation that is not a multiple of 3 and changes the entire downstream sequence of amino acids?

Frameshift

List the types of mutation from least severe impact to most severe impact.

Silent < Missense < Nonsense < Frameshift

What is a reading frame?

The order of triplet codons

A single nucleotide deletion in the middle of a gene would most likely result in:

A frame-shift mutation affecting the entire downstream protein

What type of inheritance pattern has vertical transmission, affecting multiple generations with male-male transmission being possible?

Autosomal dominant

What type of inheritance pattern has horizontal transmission, occurring usually from heterozygous parents & typically affects only a single generation?

Autosomal recessive

What chance does each offspring have of inheriting the affected phenotype of an autosomal dominant condition if a heterozygous person mates with an unaffected person?

50%

What type of inheritance pattern affects both sexes, but females MC, with affected fathers passing to 100% of daughters, and often is lethal in males?

X-linked dominant

What type of inheritance pattern primarily affects males through carrier mothers and has no father-to-son transmission?

X-linked recessive

A 25-year-old woman is concerned about her family history. Her father and paternal grandfather both developed symptoms in their 40s including progressive movement problems and cognitive decline. What inheritance pattern is most likely?

Autosomal dominant

A couple comes for preconception counseling. They are first cousins and want to know about genetic risks. What would you tell them about their increased risk?

They have an increased risk for autosomal recessive conditions

What does consanguinity increase the risk for?

Rare autosomal recessive conditions

How are the offspring affected if both parents are carriers of an autosomal recessive condition?

25% affected, 50% carriers, 25% normal

How are the offspring affected if the mother is a carrier of an X-linked recessive condition?

50% of sons affected, 50% of daughters carriers

What is Mendel’s law of segregation?

Each person possesses 2 genes for a particular characteristic, only one of which can be transmitted at any one time

What are Robertsonian translocations?

2 acrocentric chromosomes (13, 14, 15, 21, 22) join at centromeres → results in 45 chromosomes but normal phenotype

What is trisomy?

Extra chromosome

What is aneuploidy?

Gain or loss of chromosomes

What is monosomy?

Missing single chromosome from a diploid pair

What is the MC viable autosomal trisomy?

Down syndrome (Trisomy 21)

The following characteristics are seen in what condition?

• heart defects

• intellectual disability

• up slanting palpebral fissures

• flattened nasal bridge

• brush field spots

• epicanthal fold

• increased risk of leukemia

Down syndrome (Trisomy 21)

The following characteristics are seen in what condition?

• short stature

• webbed neck

• broad chest, widely spaced nipples

• CoA

• normal intelligence

• primary amenorrhea (streak ovaries)

• lymphedema

Turner Syndrome (45, X)

The following characteristics are seen in what condition?

• tall stature

• gynecomastia

• hypogonadism

• infertility

• learning difficulties

Klinefelter syndrome (47, XXY)

A 16 y/o girl is brought to the physician by her mother due to concerns that she has not yet started menstruating. She has always been significantly shorter than her peers. She is performing well academically in the 10th grade & has good social relationships. On PE, her height is below the 3rd percentile. She has a low posterior hairline, a webbed neck and a broad, shield-like chest with widely spaced nipples. What is the most likely diagnosis?

Turner Syndrome (45, X)

What is the management for Turner Syndrome (45, X)?

Exogenous estrogen-progestin & echo to r/o CoA

The following characteristics are seen in what condition?

• intellectual disability

• large/prominent ears

• autism spectrum behaviors

• macroorchidism

• Xq27.3; FMR1 gene

Fragile X Syndrome

The following characteristics are seen in what condition?

• “cocktail party” personality

• supravalvular AS

• elfin facial features

• hypercalcemia

• 7q11.23 deletion

Williams Syndrome

The following characteristics are seen in what condition?

• CHD

• immunodeficiency

• cleft palate

• hypocalcemia

• 22q11.2 deletion

DiGeorge Syndrome

What condition is a maternal deletion of 15q11.2?

Angelman Syndrome

What condition is a paternal deletion of 15q11.2?

Prader-Willi Syndrome

What features are seen with a 1p36 deletion?

Intellectual disability, seizures, & growth problems

Two unrelated children present with deletions affecting the same region of chromosome 15 (15q11.2–q13), yet they have dramatically different clinical features. What syndrome does each child have?

• Child A: History of poor feeding in infancy, now obese with an insatiable appetite

• Child B: Exhibits inappropriate laughter, seizures, and severe intellectual disability

Child A: Prader-Willi; Child B: Angelman

What is the percentage of people with a disease genotype who show the phenotype?

Penetrance

What term refers to the range of severity in people with the same genetic condition?

Variable expressivity

What is the MCC of inherited intellectual disability?

Fragile X Syndrome

What type of inheritance pattern does fragile X syndrome display?

X-linked dominant

Why might female carriers look different from affected males with fragile X syndrome?

Reduced penetrance & variable expressivity

What genetic testing method is best for chromosome number / structure?

*ex: Down syndrome diagnosis

Karyotype

What genetic testing method is best for small deletions / duplications?

*ex: Autism evaluation

Microarray

What genetic testing method is best for specific deletions?

*ex: DiGeorge syndrome

FISH

What genetic testing method is best for enzyme deficiencies?

*ex: PKU screening

Biochemical

FISH would be the most appropriate initial test for:

Suspected DiGeorge syndrome based on clinical features

What are clinical applications of PCR?

Mutation detection, viral load testing, paternity testing, forensic analysis, research applications

What type of genetic testing amplifies DNA for analysis & makes millions of copies from tiny samples?

PCR

What are the best applications for biochemical analysis?

IEM, enzyme deficiency diseases, newborn screening FU, monitoring treatment response

Which genetic testing method would be most appropriate for evaluating a child with multiple congenital abnormalities and unexplained intellectual disability?

Chromosome microarray

What is the most critical teratogen period?

3-16 weeks gestation (organogenesis)

What teratogen causes neural tube defects & cognitive effects?

VPA

What teratogen causes growth restriction, facial dysmorphology, & CNS effects?

Alcohol

What teratogen causes multiple malformations and requires 2 forms of contraception?

Isotretinoin

What teratogen causes renal dysplasia in the 2nd/3rd trimester?

ACE inhibitors

What matters more for teratogens— dose or timing?

Timing

What is the safety protocol for isotretinoin?

Pregnancy test before initiation & monthly during treatment, 2 forms of contraception requiring during treatment, & stop meds 1 month before attempting conception

What patients should genetic screening be offered to?

All pregnant women regardless of age

What prenatal tests are diagnostic but carry procedural risks?

CVS or amniocentesis

What is a screening test that detects trisomies 13, 18, 21 & sex chromosome aneuploidies, and has higher detection rates than traditional serum screening?

Cell-free DNA

What conditions are universally recommended to screen for carriers?

CF, spinal muscular atrophy, hemoglobinopathies

What conditions are ethnicity-specific when deciding to screen for carriers?

Tay-Sachs (Ashkenazi Jewish, French Canadian)

Sickle Cell (African American)

Thalassemias (Mediterranean, Asian)

After negative carrier screening for cystic fibrosis, a patient's residual risk of being a carrier is:

Reduced but not eliminated

What type of conditions should you think of when you see the following?

• Neuro sx: seizures, developmental delay, hypotonia

• GI sx: vomiting, poor feeding, hepatomegaly

• Unusual odors: maple syrup, musty, fruity

• Metabolic acidosis w/ hyperammonemia

• FHX of early infant deaths

IEM

What is the primary goal of newborn screening?

Detect disorders before they become symptomatic

How can you prevent intellectual disability with PKU?

Dietary management

How can you prevent developmental delays with congenital hypothyroidism?

Thyroid hormone

How can you prevent infections with sickle cell disease?

Prophylactic antibiotics

The combination of metabolic acidosis and hyperammonemia in a newborn most likely suggests:

Inborn error of metabolism

What is a classic presentation of a metabolic emergency, which can cause rapid neurological damage?

Metabolic acidosis & hyperammonemia

A 32 y/o woman, currently 10 wks pregnant, presents to the clinic w/ her husband. They’re concerned bc there is a FHx of CF on her husband's side & his nephew is affected. During their prenatal visit, they ask about carrier screening, stating, “We want to know our risks.” What would you discuss with them?

Explain autosomal recessive inheritance, discuss carrier testing options, and explain residual risk even after negative testing

A 28 y/o woman presents for genetic counseling. Her father has Huntington disease, & she is now considering predictive genetic testing. She’s seeking guidance on whether to undergo testing and what the implications might be for her. What do you advise?

Huntington is autosomal dominant with complete penetrance → 50% chance the daughter inherited the gene; if she is positive, her children will have a 50% risk of being affected

What produces visible karyotypes to asses chromosomal structure?

G-banding

What is considered advanced maternal age?

35 y/o at delivery

How are mitochondrial disorders transmitted?

Exclusively through maternal line (all mitochondrial DNA is maternally inherited)

What kind of condition should you consider if there is no male-to-male transmission?

X-linked