Overview of the Diagnostic Approach in the Pediatric Genetics Clinical Setting

Question 1

You are caring for a 5 yr old boy with multiple congenital anomalies with suspected
genetic contribution.
You ordered chromosome microarray analysis, which revealed a 3.4 Mb deletion of
the 17pter and 5.6 Mb duplication of the 17qter. Which of the following parental
chromosomal abnormalities is most likely to lead to this finding?
A. balanced reciprocal translocation
B. balanced Robertsonian translocation
C. isochromosome
D. pericentric inversion
E. paracentric inversion

Answer 1

D - pericentric inversion

not balanced reciprocal trnaslocation because it would be 2 different chromosomes
not balanced Robertsonian translocation because it’s not acrocentric chromosomes
not isochromosome becaue entire arm of p or q would be missing
not paracentric becuase on two different arms of the chromsome I think.

Question 2

You are evaluating a child with lissencephaly (brain anomaly), microcephaly, dysmorphic features, cardiac malformations, hypoplastic male external genitalia, growth retardation, and intellectual disability with seizures and EEG abnormalities.
You ordered chromosome microarray analysis (CMA), and the results showed a 2.5
Mb duplication of 10pter and a 3.4 Mb deletion of 17pter. What parental chromosome abnormality is likely to result in such CMA result in the child?
A. Balanced insertion
B. Balanced paracentric inversion
C. Balanced pericentric inversion
D. Balanced reciprocal translocation
E. Robertsonian translocationrsion

Answer 2

D. Balanced reciprocal translocation because it is a deletion and duplication of 2 different chromsomes

Question 3

When there is a balanced translocation (between 2 chromosomes) in order for pairing up in meiosis to occur, a quadrivalent alignment happens. The gametes that result from this ‘pairing’ of 4 chromosomes is….

Answer 3

Adjacent-1 and Adjacent-2 segregation result in unbalanced gametes. Alternate segregation results in normal or balanced gametes.
In alternate segregation:
non-homologous
centromeres travel to
opposite poles (leads to
gametes with a complete
genetic complement)
In adjacent-1, homologous
centromeres travel to
separate daughter cells
In adjacent-2(uncommon)
adjacent chromosomes with
homologous centromeres go
to the same daughter cell

Question 4

Explain the following findings in a child :
* arr1q44(245956212-249212668)x1
* arr18q22.2q22.3(67832679-71931611)x1
Mother is asking about recurrence risk, of note she now has a different partner.
What would be the next step ?

Answer 4

• test the parents
• these are small deletions so CMA would be best test
• FISH would be option too since we know what we are looking for

Question 5

FISH testing done after CMA result of child.

Maternal:
* ish1q44(RP11-230L4x2)
* ish18q22.3(RP11-630H13x1)
Paternal:
* ish1q44(RP11-230L4x2)
* ish18q22.3(RP11-630H13x2)
Explain what method was used, what are the findings and what is the recurrence
risk for future pregnancies

Answer 5

• FISH probes made from child’s DNA
• Mom has 1 deletion that is in the child, so recurrence risk = 50%
• The other deletion is de novo, so recurrence risk = 1-2%

Question 6

What testing should be ordered for multiple congenital anomalies?

Answer 6

WES/CMA or WGS as 1st or 2nd tier
it is recommended to go broad

Question 7

In the NICU setting is often best to go with what testing?

Answer 7

rapid genome
if specific you can go with panel however if kid is deteriorating this could be wasting time if you are not sure

Question 8

When to order karyotype?

Answer 8

Mainly used for aneuploidies, to look for translocations (e.g.
Robertsonian translocation for down syndrome), or other rearrangements (ring
chromosome, isochromosome)

Question 9

When to order CMA?

Answer 9

can be used as first tier for multiple congenital anomalies/DD/ID/learning
disability/Autism Spectrum/dysmorphic features/behavioral concerns, or when there is concern for specific CNV diagnosis (22q11.2 etc)
- issue with CMA is that it’s a start. if only CMA done and nothign found other can think genetic testing was done adn no further testing is needed.

I don’t think Dr. Tallis would recommend that we order CMA alone? I’m not sure.

Question 10

Multiple congenital anomalies/DD/ID/learning disability/Autism Spectrum
Disorders- per ACMG practice guidelines
What test to order?

Answer 10

go broad with CMA/WES or WGS

Question 11

Is mitochondrial DNA sequencing included in WGS?

Answer 11

Mitochondrial DNA sequencing is included in WGS

Question 12

When is the only time it is appropriate to order single gene testing?

Answer 12

known familial mutation

Question 13

When is the use of panels appropriate?

Answer 13

Use of panels can be more prevalent when evaluating adults versus infants/children, as the phenotype is often clearer
panels shoudl include sequencing and del/dup anlysis

Question 14

VUS rate is actually higher with panels in comparison with WGS/WES. Why is this?

Answer 14

The lab reports everything they find in a panel. WGS/WES would find too many to report them all. Only report what is relevant to reporting criteria.

Question 15

Unexpected findings including secondary findings are more common with broader
testing (WES/WGS)

Answer 15

Just improtant to remember.

Question 16

What is the size of an indel?

Answer 16

1bp – 1kB = indel

Question 17

Severity of OI

Answer 17

most severe II,III,IV,I least sever