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x_NeuroGenetics Review > Making Sense of Genetic Testing > Flashcards

Making Sense of Genetic Testing Flashcards

1
Q

Different types of Lab tests. What falls under the following:

  • Cytogenic
  • DNA
  • Metabolic
A

Cytogenic

  • G-bands
  • CMA: Oligo, SNP

DNA:

  • Sequence
  • Methylation
  • Southern
  • NGS; WholeExome disorder panel

Metabolic

  • Mass spec
  • Analyte
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2
Q

What genetic test is done for (known) Down syndrome child?

A
  • Chromosome analysis/karyotype (to know recurrence test)
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3
Q

What is seen here?

A

46,XY,der(21;21)(q10;q10)

  • This causes Down syndrome phenotype
  • 21q21q translocation
  • If the parent has this translocation, recurrence risk is 100%
  • Parent would possibly be 45,XY,der(21;21)(q10;q10)
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4
Q

What is seen here?

A

45,XY,der(21;21)(q10;q10)

  • Translocation carrier for 21q21q
  • 100% recurrence risk of Down’s in children
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5
Q

What are take home points for Down syndrome testing

A

Always get a chromosome analysis (G-banded)

  • Clinical diagnosis and/or array CGH are NOT good enough Recurrence risk for t(21;21) carrier is 100%
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6
Q

T/F: The prognosis for child with Down’s due to translocation is slightly different form non-translocation type

A

False; same prognosis

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7
Q

What is the resolution of G-banded chromosomes?

A

Really only ~4MB

  • Less for duplications
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8
Q

What is FISH?

  • Mechanism
  • When is it used/what can it detect
A

Fluorescence in situ hybridization (FISH)

  • Fluorescent probes bind to specific sequences of DNA
  • Under a special microscope these probes glow
  • Can detect deletions, duplications (to a lesser extent), and translocations.
  • ONLY at regions of PROBE of INTEREST!
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9
Q

What is Rapid FISH?

  • What does it detect
  • When are results available
A

Rapid FISH (Aneuvysion)

  • Can detect aneuploidy of chromosomes 13, 18, 21, X and Y chromosomes
  • Results available in 2-3 days
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10
Q

What is chromosomal microarray?

  • Detects what
A

Array comparative genomic hybridization (aCGH)

  • Oligo array
  • SNP array

Detection:

  • Detects extra or missing pieces of DNA
  • Can detect deletion/duplication of 5-10 Kb
  • Deletions and duplications detected equally well.
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11
Q

What is oligo array vs. snap array?

A
  • Oligo: copy number only (if 0, means copy number neutral)
  • SNP: copy number and AOH (absence of heterozygosity)
  • AOH could be due to deletion or UPD (uniparental disomy)
  • In below picture, you have no midline dots: AOH
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12
Q

What genetic is testing for this child:

  • Low, but normal birth weight
  • Poor feeding and failure to thrive in infancy
  • Developmental delay
  • Behavioral problems (hyperactivity, atypical)
  • Non-dysmorphic
  • No congenital abnormalities
  • Cognitive testing: mild ID to Borderline range

What would genetic testing find? What condition is this?

A
  • Tested because of cognitive findings
  • This is due to duplication 17p11.2, Potocki–Lupski syndrome
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13
Q

What is the typical phenotype of Potocki-Lupski syndrome?

A
  • Patients often non-dysmorphic
  • Variable phenotype:
  • No congenital anomalies to HLHS
  • Improved learning and behaviour with therapy.
  • Long term follow up for aortic root dilation.
  • Heart problems may involve L heart hypoplasia; can be really bad
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14
Q

What genetic testing may come back normal for Potocki-Lupski syndrome?

A

Typically normal:

  • Chromosomal analysis
  • FISH
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15
Q

What is the genetic cause of Potocki-Lupski syndrome?

A

Duplication 17p11.2

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16
Q

Case)

  • A 36-year-old woman undergoes a CVS in the 12th week of pregnancy.
  • The results of the chromosome analysis reveal 47,XY,+15 and an amniocentesis is recommended.
  • The results of the amniocentesis reveal a normal 46,XY complement. The couple is reassured.
  • Several months later, you receive a call from the NICU to evaluate this couple’s newborn who has severe hypotonia and requires mechanical ventilation and tube feeding
  • What condition do you suspect?
  • What genetic test do you want?
A

Suspect Prader-Willi/Angelman

  • Methylation studies
  • SNP microarray
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17
Q

What does this mean for suspected Prader-Willi/Angelman kid?

A
  • SNP microarray: shows LOH but COPY neutral (copy neutral means no deletion; thus this is caused by UPD)
  • Thus, Prader-Willi syndrome due to maternal UPD15
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18
Q

If chromosome 15 showed LOH in SNP microarray, is it more probable from maternal or paternal parent?

A

Statistically, more commonly maternal

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19
Q

What genetic tests would be normal if Prader-Willi syndrome is caused by maternal UPD15 (not deletion)? Abnormal?

A

Normal:

  • G-banded chromosomes
  • OligoArray

Abnormal

  • SNP microarray
  • Methylation studies
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20
Q

What is seen here?

A

Example of Methylation study

  • Abnormal here (due to Prader-Will syndrome with maternal UPD15)
21
Q

T/F: Deletion causing PW/AS will have normal methylation studies

A

False

  • Deletion causing PW/AS will have abnormal methylation studies
22
Q

What do you do if your diagnosis is Angelman syndrome but methylation studies are normal?

A

Look for UBE3A point mutation

23
Q

What is the “new” gene for Prader-Willi-like syndrome?

  • Methylation study results?
A

Schaaf-Yang syndrome

  • Normal methylation results
  • Still unknown % due to MAGEL2 point mutation
24
Q

What is your genetic test for Multiple Congenital Anomalies as indicated by:

  • 4 yo male with devo delay and dysmorphic features
  • PMH: failure to thrive, poor feeding
  • PSH: VSD repair, hypospadius repair, orchiopexy, removal of 6th finger L hand, syndactyly
  • FHx of stillborn and SAb
A

Would want to make clinical diagnosis and do analyte testing

25
Q

What condition are you thinking with these features:

  • 4 yo male with devo delay and dysmorphic features
  • PMH: failure to thrive, poor feeding
  • PSH: VSD repair, hypospadius repair, orchiopexy, removal of 6th finger L hand, syndactyly
  • FHx of stillborn and SAb
A

Smith-Lemli-Opitz syndrome

26
Q

How do you diagnose Smith-Lemli-Opitz syndrome?

A

Clinically and then with analyte testing (rather than expensive WholeExome sequencing)

  • Defect in cholesterol biosynthesis
  • Sterol profile abnormal
  • d7-dehydrocholesterol reductase mutation analysis for carrier/prenatal
27
Q

What is the inheritance pattern for S-L-O?

  • Recurrence risk
A
  • Autosomal recessive
  • Recurrence risk 25%
28
Q

What are the take home points for malformation syndromes/SLO?

A
  • Not all malformation syndromes are “chromosomal”
  • Family history (miscarriages) may provide a clue to mode of inheritance
  • Rapid testing necessary when patient not stable:
  • ANALYTE TESTING: STEROL ANALYSIS SINGLE GENE SEQUENCING
  • Recurrence risk for SLO is 25%!!!
29
Q

What condition are you thinking with:

  • 4 yo boy with DD, hypotonia
  • Chromosome analysis and aCGH sent by PCP are normal
  • Metabolic studies and WES sent by neuro are normal
  • Genetics takes family history
A

Thinking this is Fragile X syndrome

30
Q

What genetic testing do you want to do for Fragile X?

A

Southern blot- used for trinucleotide repeats

31
Q

What is the process of southern blot testing?

A
  • PCR
  • Enzymes cleave DNA into smaller pieces
  • Electrophoresed on a gel (larger pieces move more slowly)
  • Radio-labeled primers added that bind to target DNA sequences
32
Q

What is seen here?

A

Ex of Fragile X Southern Blot

33
Q

What condition are you thinking for:

  • 7 mo girl w/ progresive macrocephaly

Physical examination

  • alert and playful infant
  • fontanelle soft
  • mild generalized hypotonia
  • normal CNs; normal DTRs CT of brain shows large bilateral subdural hematomas
A

Glutaric aciduria type I- this is a metabolic disorder

34
Q

What are nuances of exam you want to do with “Non-accidental trauma” suspected in pt?

A
  • Ophthalmic exam
  • Skeletal survey

Contact CPS

35
Q

What genetic test do you want to do here (not suspecting MCA syndrome), but rather a metabolic disorder?

A

Analyte testing!

36
Q

What are basic and specialized components of analyte testing (done for suspected metabolic disorders)

A

Basic

  • Ammonia
  • Lactate

Specialized

  • Plasma amino acids
  • Urine organic acids
  • Acylcarnitine profile
37
Q

What does plasma AAs test detect

  • Diagnostic for what conditions
A

Detects the levels of AAs in the blood

Diagnosis of some inborn errors of metabolism:

  • Maple Syrup Urine Disease (MSUD)
  • PKU
  • Tyrosinemia
  • Urea Cycle Disorders
38
Q

What does urine organic acid test detect

  • Diagnostic for what conditions
A

Detects presence of organic acids in the urine

Diagnoses some inborn errors of metabolism

  • Organic acidemias
  • Propionic Acidemia
  • Methylmalonic Acidemia
  • Isovaleric Acidemia
39
Q

What does an acylcarnitine profile detect?

  • Diagnostic for what conditions
A

Detects levels of acylcarnitines (fatty esters bound to carnitine)

Diagnoses fatty acid oxidation disorders

  • MCAD
  • VLCAD
  • Primary carnitine deficiency
40
Q

What are expected labs for Glutaric aciduria type I?

A

Urine organic acids:

  • High glutaric acid
  • High 3-OH-GA
  • High glutaconic acid

Low plasma carnitine

41
Q

Describe Glutaric aciduria type I

  • Inheritance pattern
  • Incidence
  • Presentation
  • Symptoms
  • Prognosis
A

- Autosomal recessive

  • 1/30,000 (1/300 Amish & Ojibway-Cree)
  • NBS panel, but may be negative
  • Typically presents 6-18 months macrocephaly; poor feeding; irritable mild hypotonia; dystonia; dyskenesia
  • Mild manifestations may be overlooked
  • Prognosis variable
42
Q

Take home points for Glutaric aciduria type I

A
  • Glutaric aciduria is sneaky
  • Can be missed on NBS
  • Will be diagnosed on Urine Organic Acids
  • Can be asymptomatic in infancy
  • Can mimic NAT
  • Sometimes misdiagnosed as “CP” Is treatable
  • Carries a 25% recurrence risk
43
Q

What are you thinking with:

  • 3.5 yo female
  • “looks like skeletal dysplasia”
  • Macrocephaly, short stature
  • Chiari I malformation, obstructive hydrocephalus
  • Pulmonary valve stenosis
  • Myopia
  • FGFR3 normal What tests do you want?
A

Uncertain, Yet Likely “Genetic” Cause

  • Whole Exome Sequencing Results (not necessary anymore once more research was done on this condition)
44
Q

What is the diagnosis with the following exome sequencing results:

  • Gene: PTPN11- protein-tyrosine phosphatases nonreceptor-type 11
A

Noonan syndrome

45
Q

Describe the genetics of Noonan sydnrome

A
  • Gene: PTPN11- protein-tyrosine phosphatases nonreceptor-type 11
  • Mutation:
  • c.922A>G (p.N308D)
  • NGS call: 0/1:108:86:194
  • Heterozygous
  • Confirmed by Sanger sequencing as heterozygous
46
Q

Describe Noonan syndrome

  • Inheritance pattern
  • Symptoms
  • Dysmorphic features
A

- Autosomal dominant

  • Hypertelorism, downward eyeslant, and low-set posteriorly rotated ears, short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, epicanthic folds, deafness, motor delay, and a bleeding diathesis
47
Q

Relative genetic testing costs?

A
48
Q
A

x_NeuroGenetics Review (38 decks)

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