Genetics

Question 1

Acrocentric chromosomes have STALKS and SATELLITES

Answer 1

Stalks: ribosomal RNA, nucleolar organizing region, NORs

Satellites: repetitive, non-encoding, satellite DNA

Question 2

metacentric, submetacentric, acrocentric

what is position of centromere?

Answer 2

medial, distal, terminal!

Question 3

what is the telomere sequence?

Answer 3

TTAGGG

Question 4

Phases of prophase 1 in meiosis?

Answer 4

Lazy zebras perform dastardly deeds

Leptotene
Zygotene
Pachtytene
Diplotene
Diakinesis

Question 5

Leptotene

Answer 5

Thin DNA threads in nucleus, start looking for homologous chromosomes

Question 6

Zygotene

Answer 6

Chromosomes are pulled more tightly together

Begin to form synaptonemal complex, important for recombination

DSBs form, recombination/cross-over begin

telomere bouquet - see telomeres anchored towards outside of cell

Question 7

Pachtytene

Answer 7

Most condensed chromosomes
Synaptonemal complexes= close together

Cross over has occurred, see bivalents or tetrads

GENETIC RECOMBINATION OCCURS AT THIS STEP

Question 8

Diplotene

Answer 8

Loosening up of synamptonemal complex,

stay adhered at chiasma/chiasmata = points where crossover has occured

Question 9

Diakineses

Answer 9

Nuclear envelope starts to disintegrate
= proceed to regular steps

Question 10

Why is meiosis much longer?

Answer 10

Can be months to years

Time for crossover to occur= genetic diversity

Question 11

Meiosis 1 is the ______ division

Answer 11

Reductional

Question 12

Meiosis 2 is the ______ division

Answer 12

Equational

Question 13

What is constitutional mosaicism?

Answer 13

at least 2 cell lines with different chromosomal complement in a fetoplacental unit derived from a single zygote

amount of mosaicism - % of cells with each karyotype depends and the tissue distribution is dependent on timing of event and cell selection

Question 14

What are the three trisomies associated with survival and the name of their syndrome?

Answer 14

Trisomy 21 (Down’s syndrome)

Trisomy 18 (Edward Syndrome)

Trisomy 13 (Patau Syndrome)

*survival with 13 and 18 is not long

Question 15

Etiological factor for DS

Answer 15

Advanced maternal age is the only etiological factor for which a link with aneuploidy is unequivocally recognized.

Question 16

95% of a DS cases have a free 21.

4% of DS cases have…

Answer 16

A robertsonian translocation.

an additional 21 is translocated to chromosome 14, and two normal 21s.

(Parental karyotype shows father is a balanced carrier of the robertsonian translocation – have an increased risk of having conceptus with DS)

Question 17

3 types of balanced structural rearrangements

Answer 17

reciprocal translocation
inversion
robertsonian translocation

normal amount of DNA = likely normal phenotype. carrier is at risk of having unbalanced conception. 4% of couples who have experienced 3 or more pregnancy losses have one member who is a carrier of a translocation or an inversion.

Question 18

CML

Answer 18

Chronic myelogenous leukemia

Translocation between chromosome 9 and 22.

Fusion gene between 5’ regulatory region of BCR of 22 and ABL1 (tyrosine kinase) of 9

patients receive a targeted therapy: TK inhibitor (Imatinib/Gleevec)

Question 19

what is PKU

Answer 19

Autosomal Recessive

Phenylketonuria = buildup of phenylalanine and lack of tyrosine as a result of deficiencies in the PAH (phenylalanine hydroxylase gene), which is normally responsible for transforming phe into tyrosine

Question 20

Symptoms of PKU

Treatment?

Answer 20

Phenylalanine is neurotoxic

Intellectual disabilities
Fair Skin
Seizures
Rash

Symptoms do not start immediately at birth, a buildup of Phe is required.

Don’t eat Phe!

Question 21

Allelic heterogeneity

Answer 21

More than 1 mutation in the same gene that can cause the same phenotype

If someone has this, we call them a compound heterozygote

Same mutation: homozygote, likely if there is founder effect or consanguinity (increasing frequency of same variant)

Question 22

Locus/Genetic Heterogeneity

Answer 22

One disorder/phenotype is caused by changes in more than 1 gene

Question 23

Marfan Syndrome, inheritance

Answer 23

Autosomal Dominant

Allelic Heterogeneity (Mutations in FBN1 gene)

Pleiotropy (defects in one gene causing multiple clinical manifestations)

Full penetrance

Variable expressivity

25% of mutations occur de novo

Question 24

Clinical Features of Marfan

Answer 24

1. Tall, thin, arm span that exceeds height,
2. lens dislocation,
3. dilation of aorta,
4. pectus excavated/carinatum,
5. arachnodactyly

Question 25

Duchenne muscular dystrophy, inheritance?

Answer 25

Mutations in DMD gene, one of largest genes Lethal, boys will not live to reproductive age 1/3 of mutations occur de novo X linked recessive

Question 26

MELAS

Answer 26

mitochondrial encephalopathy, lactic acidosis and stroke-like episodes mitochondrial gene encoding tRNALeu are affected

Question 27

Prader-Willi Angelman syndrome

Answer 27

Genomic imprinting on chromosome 15 Prader: father's copy is normally expressed Angelman: mother's copy is normally expressed Cases: Deletion of relevant parent DNA, UPD of other parent, imprinting defects, UBE3A mutation for Angelman only

Question 28

3 epigenetic mechanisms

Answer 28

Determine which parts of genome should be available for transcription and which parts should be compact and inaccessible. 1. DNA methylation at CPG nucleotides 2. covalent modifications of histone proteins 3. regulation by noncoding RNAs

Question 29

Complex disorders

Answer 29

Threshold for clinical expression Polygenic and environmental/lifestyle factors PRS - polygenic risk score Incomplete Penetrance and Variable Expressivity

Question 30

Laboratory Methods: SNVs and Small indels

Answer 30

1. genotyping methods (for known variants) 2. Sanger sequencing 3. Next-generation sequencing (NGS)

Question 31

Laboratory methods Structural variants

Answer 31

1.Karyotyping > 5 Mb 2. Chromosomal microarray (5-10kb) 3. MLPA (intragenic copy number variant) - Multiplex ligation dependent probe amplification 4. NGS

Question 32

Two ways to filter found variants

Answer 32

1. genotype driven: find a variant, determine its frequency, call it clinically suspicious (helpful when identifying/considering a new gene) 2. phenotype driven - only consider genes associated to primary phenotype

Question 33

DNA sequencing in Clinical Diagnostics

Answer 33

1. Preconception 2. Prenatal 3. Newborn screening and pediatric care (hearing loss, Cystic fibrosis) 4. Adult medicine (cancer predisposition, cardiac evaluation) 5. cancer- somatic testing 6. Elderly health (Alzheimer testing)

Question 34

When should you do a single-gene test?

Answer 34

1. Minimal locus heterogeneity (CFTR for CF) 2. Distinctive clinical findings clearly pointing to a specific gene (PAH for PKU) 3. Limitations of NGS sequencing tech to detect trinucleotide repeat disorders and disorders with epigenetic abnormalities (Prader-Willi, Angelman, Huntington)

Question 35

When should you do a gene panel?

Answer 35

1. Heterogeneity 2. Disorders with overlapping phenotype-differential diagnosis 3. Disorders share one manifestation but may have completely different overall presentation 4. diseases associated with genes from a common pathway or structure

Question 36

When should you do ES/GS?

Answer 36

1. Extreme heterogeneity and de novo mutations are the major mutations 2. Two or more likely unrelated phenotypes in a patient 3. No key phenotypic feature is present at the time when the test is ordered 4. Phenotype is indistinct, and the real underlying cause is not easy to identify

Question 37

Challenges remaining in Genetic testing

Answer 37

1. Infrastructure and expertise 2. Technological & Knowledge limitations 3. Ethical legal and social implications (accidental findings, test reimbursement, inequality and genetic discrimination)