Shane 3.2 (AI): Molecular Diagnostics - Mendelian Disorders Flashcards
What percentage of live births are affected by Mendelian diseases?
0.4%
This statistic highlights the prevalence of Mendelian disorders in the general population.
How many Mendelian diseases have been identified?
> 7,400
This figure includes all known Mendelian diseases cataloged in genetic databases.
How many Mendelian diseases have been solved since 2008?
> 2000
This significant progress reflects advancements in genetic research and technologies.
What is the first successful application of exome sequencing in Mendelian disorders?
Discovery of the gene for Miller syndrome (MIM 263750)
This case marked a milestone in the use of exome sequencing for rare genetic disorders.
What is the role of DHODH mutations in Mendelian disorders?
Key enzyme in the pyrimidine de novo biosynthesis pathway
Understanding this role can help in diagnosing certain genetic conditions.
What is a significant challenge in solving very rare Mendelian disorders?
Limited sample size
Finding causative mutations can be difficult when only a few individuals are affected.
How many patients are needed to solve a Mendelian disorder?
At least 3 patients
This requirement underscores the importance of having enough data for genetic analysis.
What technological advancement has led to a huge increase in solved Mendelian disorders since 2008?
Whole genome sequencing
This technology has revolutionized the identification of genetic causes of diseases.
True or False: There is only one single gene involved in Mendelian disorders compared to multiple genes in cancer.
True
This distinction is important in understanding the genetic basis of different types of diseases.
What is the purpose of whole exome sequencing (WES) in Mendelian disorders?
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.
How many SNPs are typically found in an individual exome?
20-30,000 SNPs
This number excludes synonymous SNPs, which do not affect protein function.
What is the typical reduction in the number of variants after filtering for pathogenic variants?
Reduced to 100-500 pathogenic variants
What can sequencing 2 or 3 affected individuals achieve in variant identification?
Can reduce it down to one variant gene
What is the significance of filtering fastq files in WES?
Filters out low-quality sequences with a Q score below 20
What is variant calling in the context of WES?
The process of identifying variants in the sequenced data
What is dbSNP?
A public database that contains information on SNPs
What challenges are associated with identifying de novo variants?
They are harder to identify as parents won’t have the condition
True or False: Whole exome sequencing can only identify variants that parents also have.
False
De novo variants arise spontaneously and are not present in the parents.
Fill in the blank: The process of filtering out common variants helps to focus on _______ variants.
potentially pathogenic
What is the name of the first child saved by Next Generation DNA Sequencing?
Nicholas Volker
He was saved in 2011
At what age did Nicholas Volker start experiencing health issues?
Age 2
What severe health problem did Nicholas Volker face after a cut?
It did not heal, leading to many injuries and sepsis.
How many surgeries did Nicholas Volker undergo?
Over 100 surgeries.
What major surgery did Nicholas Volker have related to his digestive system?
Colon removal.
What genetic mutation was identified in Nicholas Volker through Exome Sequencing?
Mutation in the XIAP gene.
What condition resulted from the mutation in the XIAP gene?
Immune dysregulation syndrome.
What type of disease did Nicholas Volker develop as a result of his condition?
Early-onset, rapidly progressing inflammatory bowel disease.
What treatment did Nicholas Volker receive after the identification of his condition?
Bone marrow transplant of cells taken from umbilical cord blood.
What was the initial misdiagnosis of Nicholas Volker’s condition?
Inflammatory bowel disease (IBD).
What is the function of the XIAP gene?
X-linked inhibitor of apoptosis.
How does the XIAP gene mutation affect the immune system?
It causes a huge amount of inflammation in the colon.
What type of research was conducted to understand Nicholas Volker’s condition?
Research in mice.
What publication reported the case of Nicholas Volker?
Worthey et al. Genet Med. (2011) 13:255-62.
When can cell-free fetal DNA be detected in maternal blood?
4-5 weeks after gestation
This early detection allows for non-invasive prenatal testing.
What percentage of circulating DNA in maternal blood is typically fetal?
4-10%
This percentage increases as the pregnancy progresses.
What is the role of cell-free fetal DNA in prenatal testing?
Targeted detection of mutations
It serves as a non-invasive alternative to invasive procedures.
What procedure is being replaced by cell-free fetal DNA testing?
Amniocentesis
Cell-free fetal DNA testing is considered safer and less invasive.
What is the sensitivity of whole genome sequencing in detecting trisomies?
99%
This high sensitivity makes it an effective screening method.
Which trisomies are commonly detected through whole genome sequencing?
- Down’s (Chromosome 21)
- Chromosome 18 (Edwards Syndrome)
- Chromosome 13 (Patau Syndrome)
These conditions are serious chromosomal disorders that can be identified early.
Fill in the blank: Up to _______ of circulating DNA in the mother is fetal.
10%
This percentage can vary with pregnancy progression.
True or False: Cell-free fetal DNA testing can easily detect chromosomal disorders.
True
This method is effective in identifying various chromosomal abnormalities.
What is cell-free (cf) DNA?
DNA isolated from plasma, often used in prenatal testing.
Cell-free DNA refers to fragments of DNA that circulate in the bloodstream, which can be analyzed for genetic conditions.
In the study, how many pregnant women were involved?
11 pregnant women.
The study focused on pregnant women carrying fetuses with specific chromosomal abnormalities.
What chromosomal abnormalities were detected in the study?
Sub chromosomal duplications, deletions, translocations, mosaicism, and trisomy 20.
These abnormalities can indicate various genetic disorders in the developing fetus.
What method was used to detect chromosomal abnormalities?
Next-generation sequencing of maternal plasma.
Next-generation sequencing allows for rapid and comprehensive analysis of genetic material.
True or False: All microdeletions, duplications, translocations, and trisomy 20 were detected blindly.
True.
‘Blindly’ indicates that the testing was done without prior knowledge of the specific abnormalities present.
Fill in the blank: The study by Srinivasan et al. was published in AJ Hum _______.
Genet.
AJ Hum Genet refers to the American Journal of Human Genetics.
What is the significance of detecting fetal subchromosomal abnormalities non-invasively?
It allows for early diagnosis without risk to the fetus.
Non-invasive methods reduce the potential for complications associated with invasive testing procedures.
What percentage of the human genome consists of exons?
1% of human genome
Exons are the coding regions of genes that are expressed.
What percentage of disease-causing mutations are found in the exome?
85%
The exome refers to the portion of the genome consisting of exons.
Agilent SureSelect hybridizes DNA with what?
Biotinylated RNA baits
This technique is used for capturing specific DNA sequences for analysis.
How many samples were used in the Cancer Genome Atlas?
11,000 samples
The Cancer Genome Atlas is a project that cataloged genetic mutations responsible for cancer.
EGFR mutations are treated with what type of inhibitors?
Small molecular inhibitors/protein kinase inhibitors
These inhibitors target the Epidermal Growth Factor Receptor (EGFR) involved in cancer cell growth.
Name three drug names used for treating EGFR mutations.
- Getinib
- [Other drug names can be added here]
- [Other drug names can be added here]
Specific drugs targeting EGFR mutations may vary.
What was the first rare Mendelian disorder solved using whole exome sequencing (WES)?
Miller syndrome
Miller syndrome is a genetic disorder characterized by specific physical abnormalities.
Why is fetal DNA sequencing possible for genetic disorders?
Cell-free fetal DNA is detected in maternal blood
This technique allows non-invasive prenatal testing for genetic conditions.
