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Growth and Development > Genomics in Modern Medicine > Flashcards

Genomics in Modern Medicine Flashcards

1
Q

“Genomic medicine is a new, structured approach
to (3)
that prominently features next-generation
sequencing and analysis.”

A

disease discovery, diagnosis and management

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2
Q

Progression of Testing (4)

A
  • Sanger PCR
    • Gene by gene, exon by exon sequencing
  • Multiplexing can accommodate small panels
  • Time consuming
  • Limited to known genes/regions
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3
Q 
Building on Sanger: Human 
Genome Project (4)
A
  • Public group consisted of ~20 international labs
  • ~$2.7 billion (under budget!)
  • Private Group-Celera Genomics
  • Took 13 years for the first draft!
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4
Q

NGS =

A

Technologies that permit rapid interrogation of DNA,
up to and including entire genomes, via massively parallel
sequencing
• Technology took shape in early 2000s

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5
Q

NGS emphasizes a distinction from initial approaches that

involved sequencing

A

of one DNA strand at a time.

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6
Q

Decreasing cost and comparatively rapid results are creating
a paradigm shift in genetics; particularly in

A

monogenic

disease.

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7
Q 
Genetic variation (5)
Human Variation 0.5% = --- million base pairs!
A 
Size
Location
Impact on a codon
Impact on the protein
Impact on expression

16

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8
Q 
Relationship of (2) of 
human genomic variants
A

frequency and size

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9
Q

Single nucleotide variants
• Common:
• Rare:
• Account for about –% of all DNA changes
• Found in about – in every 100 to 300 nucleotides

A

found in >1% of population aka SNPs (can be advantageous/silent/risk associated)

<1% of population (all of the above + pathogenic)

75
1

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10
Q

In-del (3)

A
  • Insertions and deletions of up to 50-100 nucleotides
  • Occur 1/10th as often as SNV
  • 90% are 1-10 nt in length
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11
Q

CNVs (1)

A

• Least frequent but large so, in total, affect the most nucleotides

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12
Q

Sample Preparation For NGS (4)

A
  • While there are subtle differences between tests, all samples undergo library prep
  • The goal of library preparation is add primers and barcodes to identify individuals
  • Process involves fragmentingDNA
  • “Shotgun Sequencing”
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13
Q

• Each DNA fragment has: (3)

A
  • Sequencing primer
  • Adapters
  • Barcode
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14
Q

Whole Genome

• Ready for —!

A

sequencing

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15
Q

Gene Panel requires —

A

Enrichment

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16
Q

Enrichment

• Involves selecting out

A

specific regions of interest for sequencing

using capture probes

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17
Q

Cost and time considerations (3)

A
  • Pooling allows for samples to be mixed together before enrichment
  • Allows for more sequencing of targeted regions
  • Decreases costs and time per sample
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18
Q

Sequencing Instrumentation (3)

A
  • 1 Novaseq
  • 1 NextSeq 2000
  • 2 MiSeqs
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19
Q

1 Novaseq

A

• 66 genomes in 3 days

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20
Q

2 MiSeqs

A

• 96 PgX samples in ~30 Hours

21
Q

6 Sequel IIe

A

• 1 genome = 90hrs (1 instrument)

22
Q

Illumina Chemistry uses

A

Sequencing by Synthesis (SBS)

23
Q

Fluorescent nucleotides are incorporated

A

one at a time

24
Q

— excite the fluorescence, which is read by the instrument

A

Lasers

25
Q

skipped

Bioinformatics (3)

A 
• Sample preparation and 
sequencing are only a small part of 
the process
• Critical need for Bioinformatics
• Utilize custom and commercial 
software solutions
26
Q 
Small Panel (571 genes)
• ---
A

8000

27
Q

Exome

• —

A

300,000

28
Q

Whole genome

• —

A

4,000,000

29
Q

Sensitivity and Specificity for SNPs are >—% (NA12878)

A

99

30
Q

Reliably detect In-dels up to –bp

• Read length –

A

40

2x150

31
Q

Copy Number Variant detection is continually improving

• Focus on

A

exonic level deletion/duplications

32
Q

Next Generation sequencing allows for

A

diagnosis of atypical presentations that

would not have otherwise be considered

33
Q

ACMG recommends analysis of 73 genes (2)

A
  • Primarily cancer and cardiovascular syndromes

* Report results back in pediatrics!`

34
Q

Genomes offered clinically since 2015 (2)

A
  • Only 4 findings were reported in first 80 cases

* APOB, PMS2, RYR1, and TNNT2

35
Q

Inherited syndromes that affect tooth development (2)

A
  • Mineralization Defects (PHEX, DMP1, FGF23)

* Ectodermal dysplasias

36
Q

Hypo/Oligodontia

• —

A

PAX9

37
Q

Enamel defects

• —

A

Amelogenesis Imperfecta (ENAM)

38
Q

CPGM has sequenced over — DNA samples

• Continually increasing

A

13,000

39
Q

Clinical and research testing for — disease

A

Mendelian

40
Q

Average Diagnostic Rate of ~—%

A

30

41
Q

Amelogenesis Imperfecta (3)

A

• Several forms of autosomal dominant enamel
dysplasia
• At least 18 genes associated with non-syndromic
AI
• Prevalence ranges from 1/700 to 1/14,000

42
Q

Several forms of autosomal dominant enamel

dysplasia (2)

A

• Enamel hypoplasia or hypocalcification

43
Q

At least 18 genes associated with non-syndromic

AI, including: (3)

A
  • AMELX (Amelogenin)
  • AMTN (Amelotin)
  • ENAM (Enamalin)
44
Q

skipped
Queried public databases for variants in three genes
• CPGM- — samples in public warehouse
• gnomAD- ~— genomes and exomes

A

7365
145,000

None were referred for a primary dental concern
• Limited to predicted loss of function variants with a
MAF<1%

45
Q 
Analysis of 3 genes identified 95 variants
• Amelogenin = --- variants 
• Amelotin = --- variants
• Enamelin = --- variants
• Estimated prevalence of ~1/527
• Unrecognized disease?
• Non-penetrance/variable expressivity
A

7
20
68

46
Q

Amelogenesis Imperfecta is diagnosed clinically

• Clinical impact? (2)

A
  • Earlier and more frequent screening

* Novel treatments

47
Q

Common Barriers (3)

A 
• Identified a need for more 
education
• Justification of testing
• Changing landscape
   • Patients will ask for it
48
Q

— permits a new way of molecular diagnosis

• Panels, ES, GS

A

NGS

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