Shane 3.2 (AI): Molecular Diagnostics - Mendelian Disorders

Question 1

What percentage of live births are affected by Mendelian diseases?

Answer 1

0.4%

This statistic highlights the prevalence of Mendelian disorders in the general population.

Question 2

How many Mendelian diseases have been identified?

Answer 2

> 7,400

This figure includes all known Mendelian diseases cataloged in genetic databases.

Question 3

How many Mendelian diseases have been solved since 2008?

Answer 3

> 2000

This significant progress reflects advancements in genetic research and technologies.

Question 4

What is the first successful application of exome sequencing in Mendelian disorders?

Answer 4

Discovery of the gene for Miller syndrome (MIM 263750)

This case marked a milestone in the use of exome sequencing for rare genetic disorders.

Question 5

What is the role of DHODH mutations in Mendelian disorders?

Answer 5

Key enzyme in the pyrimidine de novo biosynthesis pathway

Understanding this role can help in diagnosing certain genetic conditions.

Question 6

What is a significant challenge in solving very rare Mendelian disorders?

Answer 6

Limited sample size

Finding causative mutations can be difficult when only a few individuals are affected.

Question 7

How many patients are needed to solve a Mendelian disorder?

Answer 7

At least 3 patients

This requirement underscores the importance of having enough data for genetic analysis.

Question 8

What technological advancement has led to a huge increase in solved Mendelian disorders since 2008?

Answer 8

Whole genome sequencing

This technology has revolutionized the identification of genetic causes of diseases.

Question 9

True or False: There is only one single gene involved in Mendelian disorders compared to multiple genes in cancer.

Answer 9

True

This distinction is important in understanding the genetic basis of different types of diseases.

Question 10

What is the purpose of whole exome sequencing (WES) in Mendelian disorders?

Answer 10

To identify pathogenic variants responsible for genetic conditions

WES focuses on the coding regions of the genome, which are most likely to contain disease-causing mutations.

Question 11

How many SNPs are typically found in an individual exome?

Answer 11

20-30,000 SNPs

This number excludes synonymous SNPs, which do not affect protein function.

Question 12

What is the typical reduction in the number of variants after filtering for pathogenic variants?

Answer 12

Reduced to 100-500 pathogenic variants

Question 13

What can sequencing 2 or 3 affected individuals achieve in variant identification?

Answer 13

Can reduce it down to one variant gene

Question 14

What is the significance of filtering fastq files in WES?

Answer 14

Filters out low-quality sequences with a Q score below 20

Question 15

What is variant calling in the context of WES?

Answer 15

The process of identifying variants in the sequenced data

Question 16

What is dbSNP?

Answer 16

A public database that contains information on SNPs

Question 17

What challenges are associated with identifying de novo variants?

Answer 17

They are harder to identify as parents won’t have the condition

Question 18

True or False: Whole exome sequencing can only identify variants that parents also have.

Answer 18

False

De novo variants arise spontaneously and are not present in the parents.

Question 19

Fill in the blank: The process of filtering out common variants helps to focus on _______ variants.

Answer 19

potentially pathogenic

Question 20

What is the name of the first child saved by Next Generation DNA Sequencing?

Answer 20

Nicholas Volker

He was saved in 2011

Question 21

At what age did Nicholas Volker start experiencing health issues?

Answer 21

Age 2

Question 22

What severe health problem did Nicholas Volker face after a cut?

Answer 22

It did not heal, leading to many injuries and sepsis.

Question 23

How many surgeries did Nicholas Volker undergo?

Answer 23

Over 100 surgeries.

Question 24

What major surgery did Nicholas Volker have related to his digestive system?

Answer 24

Colon removal.

Question 25

What genetic mutation was identified in Nicholas Volker through Exome Sequencing?

Answer 25

Mutation in the XIAP gene.

Question 26

What condition resulted from the mutation in the XIAP gene?

Answer 26

Immune dysregulation syndrome.

Question 27

What type of disease did Nicholas Volker develop as a result of his condition?

Answer 27

Early-onset, rapidly progressing inflammatory bowel disease.

Question 28

What treatment did Nicholas Volker receive after the identification of his condition?

Answer 28

Bone marrow transplant of cells taken from umbilical cord blood.

Question 29

What was the initial misdiagnosis of Nicholas Volker's condition?

Answer 29

Inflammatory bowel disease (IBD).

Question 30

What is the function of the XIAP gene?

Answer 30

X-linked inhibitor of apoptosis.

Question 31

How does the XIAP gene mutation affect the immune system?

Answer 31

It causes a huge amount of inflammation in the colon.

Question 32

What type of research was conducted to understand Nicholas Volker's condition?

Answer 32

Research in mice.

Question 33

What publication reported the case of Nicholas Volker?

Answer 33

Worthey et al. Genet Med. (2011) 13:255-62.

Question 34

When can cell-free fetal DNA be detected in maternal blood?

Answer 34

4-5 weeks after gestation ## Footnote This early detection allows for non-invasive prenatal testing.

Question 35

What percentage of circulating DNA in maternal blood is typically fetal?

Answer 35

4-10% ## Footnote This percentage increases as the pregnancy progresses.

Question 36

What is the role of cell-free fetal DNA in prenatal testing?

Answer 36

Targeted detection of mutations ## Footnote It serves as a non-invasive alternative to invasive procedures.

Question 37

What procedure is being replaced by cell-free fetal DNA testing?

Answer 37

Amniocentesis ## Footnote Cell-free fetal DNA testing is considered safer and less invasive.

Question 38

What is the sensitivity of whole genome sequencing in detecting trisomies?

Answer 38

99% ## Footnote This high sensitivity makes it an effective screening method.

Question 39

Which trisomies are commonly detected through whole genome sequencing?

Answer 39

* Down's (Chromosome 21) * Chromosome 18 (Edwards Syndrome) * Chromosome 13 (Patau Syndrome) ## Footnote These conditions are serious chromosomal disorders that can be identified early.

Question 40

Fill in the blank: Up to _______ of circulating DNA in the mother is fetal.

Answer 40

10% ## Footnote This percentage can vary with pregnancy progression.

Question 41

True or False: Cell-free fetal DNA testing can easily detect chromosomal disorders.

Answer 41

True ## Footnote This method is effective in identifying various chromosomal abnormalities.

Question 42

What is cell-free (cf) DNA?

Answer 42

DNA isolated from plasma, often used in prenatal testing. ## Footnote Cell-free DNA refers to fragments of DNA that circulate in the bloodstream, which can be analyzed for genetic conditions.

Question 43

In the study, how many pregnant women were involved?

Answer 43

11 pregnant women. ## Footnote The study focused on pregnant women carrying fetuses with specific chromosomal abnormalities.

Question 44

What chromosomal abnormalities were detected in the study?

Answer 44

Sub chromosomal duplications, deletions, translocations, mosaicism, and trisomy 20. ## Footnote These abnormalities can indicate various genetic disorders in the developing fetus.

Question 45

What method was used to detect chromosomal abnormalities?

Answer 45

Next-generation sequencing of maternal plasma. ## Footnote Next-generation sequencing allows for rapid and comprehensive analysis of genetic material.

Question 46

True or False: All microdeletions, duplications, translocations, and trisomy 20 were detected blindly.

Answer 46

True. ## Footnote 'Blindly' indicates that the testing was done without prior knowledge of the specific abnormalities present.

Question 47

Fill in the blank: The study by Srinivasan et al. was published in AJ Hum _______.

Answer 47

Genet. ## Footnote AJ Hum Genet refers to the American Journal of Human Genetics.

Question 48

What is the significance of detecting fetal subchromosomal abnormalities non-invasively?

Answer 48

It allows for early diagnosis without risk to the fetus. ## Footnote Non-invasive methods reduce the potential for complications associated with invasive testing procedures.

Question 49

What percentage of the human genome consists of exons?

Answer 49

1% of human genome ## Footnote Exons are the coding regions of genes that are expressed.

Question 50

What percentage of disease-causing mutations are found in the exome?

Answer 50

85% ## Footnote The exome refers to the portion of the genome consisting of exons.

Question 51

Agilent SureSelect hybridizes DNA with what?

Answer 51

Biotinylated RNA baits ## Footnote This technique is used for capturing specific DNA sequences for analysis.

Question 52

How many samples were used in the Cancer Genome Atlas?

Answer 52

11,000 samples ## Footnote The Cancer Genome Atlas is a project that cataloged genetic mutations responsible for cancer.

Question 53

EGFR mutations are treated with what type of inhibitors?

Answer 53

Small molecular inhibitors/protein kinase inhibitors ## Footnote These inhibitors target the Epidermal Growth Factor Receptor (EGFR) involved in cancer cell growth.

Question 54

Name three drug names used for treating EGFR mutations.

Answer 54

* Getinib * [Other drug names can be added here] * [Other drug names can be added here] ## Footnote Specific drugs targeting EGFR mutations may vary.

Question 55

What was the first rare Mendelian disorder solved using whole exome sequencing (WES)?

Answer 55

Miller syndrome ## Footnote Miller syndrome is a genetic disorder characterized by specific physical abnormalities.

Question 56

Why is fetal DNA sequencing possible for genetic disorders?

Answer 56

Cell-free fetal DNA is detected in maternal blood ## Footnote This technique allows non-invasive prenatal testing for genetic conditions.